Ugly Betty is the story of Betty Suarez, a good-hearted girl from Queens, New York, brave but sorely lacking in social skills, self-confidence, fashion sense, and aesthetic polish. Betty is suddenly thrust into a different world when she is hired as a personal assistant at Mode, a fashion magazine headquartered in Manhattan and part of the publishing empire of the wealthy Bradford Meade and his family. Meade hires Betty, despite being a fish out of water, to look after (and keep out of trouble from womanizing) his son, newly-installed Mode editor-in-chief Daniel Meade. As time goes by, Betty and Daniel learn to trust one another, and ultimately become friends and allies in a world sometimes beautiful and sometimes maddeningly chaotic.

A cast of characters populates their worlds. Creative Director Wilhelmina Slater, who wanted the Editor-In-Chief position, is Daniel's nemesis, while Betty finds herself dealing with Marc St. James, Wilhelmina's assistant/henchman and receptionist Amanda Sommers (originally Tanen until the end of the first season), who wanted Betty's job in large part, initially, because of her attraction to Daniel. The only friends that Betty trusts at Mode are seamstress Christina McKinney and accountant Henry Grubstick, to whom Betty is attracted; meanwhile, at home she relies on her father Ignacio Suarez, older sister Hilda and Hilda's son Justin. Daniel's family, includes his mother Claire Meade; and, after returning from a two-year disappearance, his transsexual and competitive sister Alexis Meade (formerly known as Alex), who has made a successful transition to being female. Betty sports thick-framed eyeglasses and a large and prominent set of dental braces (which have become the most identifiable symbol for both Ferrera's character and the show itself). Her lackluster physical appearance and awkward nature result in her immediately being singled out in the single-minded world of New York City fashion, and she is quickly saddled with the show's eponymous nickname. The show contains a degree of surrealism used to express the inner thoughts of its characters. For example, in "I See Me, I.C.U.", Betty speaks with an earlier version of herself about how far she has come since her first day.

Throughout the show's first season, most of the serialized storylines revolve around Betty trying to balance her work, home and romantic life. Betty's relationship with boyfriend Walter is challenged; initially, Walter resists the changes in Betty's life. Betty must deal with Walter's infidelity with obnoxious neighbor Gina Gambarro. Betty falls in love with Mode accountant Henry Grubstick, whose ex-girlfriend Charlie claims to be pregnant with his child, despite having cheated with another man. Betty's sister Hilda fails to sell beauty products door-to-door and becomes unemployed, but discovers her talent as a beautician. Betty's father Ignacio has health and immigration problems, and he admits to a history of murdering his employer after finding out he abused his wife, Rosa, with whom he had fallen in love. Rosa is Betty and Hilda's late mother.

Other Season One plot lines involve Daniel's womanizing, his affairs with fellow editor Sofia Reyes and lawyer Grace Chin, and his sudden drug addiction; Bradford's affair with Daniel's late predecessor Fey Sommers; the revelation that Claire murdered Fey; Claire's battle with alcoholism; and Alexis' attempts to repair her relationship with Daniel at Bradford's expense. Several storylines revolve around Wilhelmina, including her schemes to use Alexis to force Daniel out of his job. (Alexis is first introduced as 'the mystery woman', until she reveals to the world that Alex Meade had not died in a skiing accident but was now a woman, Alexis). Wilhelmnia also plots to marry Bradford so she can take over the company, and she attempts to deal with her rebellious daughter Nico while winning acceptance from her father.

Finally, Marc deals with multi-tasking for his boss, his homosexuality and family acceptance. Amanda becomes a binge eater, is the target of a prank, and discovers that her true birth mother was Fey Sommers. Christina is used by Wilhelmina even as she helps Betty.

The 2nd season of Ugly Betty began on September 27, 2007, and ended on May 22, 2008. The season's theme was "Brighter, Bolder, Bettyer" with a reworked version of Mika's "Hey Betty (You Are Beautiful)" being used as the featured song in its promos. This season introduced viewers to nine new recurring characters who will be played by Freddy Rodriguez, Illeana Douglas, Alec Mapa, David Blue, John Cho, Gabrielle Union, Gene Simmons, Eddie Cibrian and Juliette Goglia, while Lorraine Toussaint continued in her role as Claire's fellow prison escapee, Yoga, as a recurring regular. Mo'Nique also appeared in a recurring regular this season as well playing weekend security chief L'Amanda.

In the second season, Betty has to decide if she still wants to be with Henry after he got Charlie pregnant, and despite the fact that he is going to leave for Tucson, AZ, in a few months (so he can be at Charlie's side and help raise the baby). In between these events, a deli shop owner named Giovanni "Gio" Rossi starts building a platonic relationship with Betty, which has Hilda, Amanda, and Henry suspecting that Gio might be trying to become the new guy in Betty's life.

Daniel recovers from a car accident but Alexis forgets the last few years of her life, including the fact that she was changed into a woman and that her father mistreated her. Bradford decides to use this to his advantage and doesn't remind Alexis of how he mistreated her; instead, he claims that he was always supportive of her. Wilhelmina's scheme to marry Bradford Meade unravels when (1) Betty learns of the affair she's having with her bodyguard (they were even together the night before the wedding) and (2) Bradford has a heart attack at the altar and later dies from it. Wilhelmina would later be fired from the company by the Meade Family.

Amanda tries desperately to find out more about her family, and with Wilhelmina's help, she gets a list of people that could be her dad, leading her to Rock legend Gene Simmons. Marc finds a partner in Cliff St. Paul, a photographer who is not as handsome, but Marc accepts him as a boyfriend anyway.

Claire Meade escapes from jail with her "friend" Yoga, and they hide away in the Hamptons. Claire is later recaptured, and thanks to a clever (and ironic) scheme by the late Fey Sommers, Claire is acquitted of her murder (Fey had poisoned Claire's perfume in an attempt to kill her, but instead it made Claire become crazy and violent, and eventually she cut Fey's brakes and killed her). Later, Claire tries her best to get her life on track; however, she fears that she may become a burden on her two children. Therefore, she launches a new magazine known as "Hot Flash", which aims to attract female readers over a certain age who have been neglected by their children and have nothing better to do. At first, Alexis Meade states there is not enough money to finance the magazine; however, using her 'resources' wisely, Claire finds ways to make the magazine work and a success.

Hilda tries to get over Santos and to start her new career as a beautician while Justin, who became an intern at Mode, tries to be more like his dad and goes into a "bad boy" phase until Hilda intervenes, prompting the two to restore their mother-son relationship.

Christina is surprised to see her ex show up, but when she learns that he has a life threatening illness and in need of money for an operation, she's determined to help. When Wilhelmina offers to pay Christina if she becomes her surrogate (by being impregnated with Bradford's sperm, which Wilhelmina went to great lengths to remove from his body so she can get control of the Meade empire), Christina agrees to carry the baby, not knowing that this latest plan has more expectant twist and turns when Wilhelmina's troubled sister Renee shows up and starts dating Daniel, resulting in Wilhelmina taking great lengths to conceal her scheme.

Hilda meets Justin's gym teacher and begins a romantic relationship with him. Daniel's son shows up from Paris, and he denies him as his son but tries to bond with him. Gio wants to take Betty to Rome for a romantic date when Henry shows up to ask her hand in marriage.

Production was halted in November 2007 due to the Writers' Strike. It was then announced the season would be cut short to 18 episodes instead of a proposed 23. New episodes did not air on U.S. television until April 24, 2008, starting with Twenty Four Candles and ending on May 22, 2008, with "Jump". This was the last episode to be produced in Los Angeles.

ABC renewed the series for a third season on February 11, 2008. In addition, production has moved to its home base of New York City from Los Angeles to make the series more realistic and to take advantage of increased tax incentives in New York. The third season premiered on September 25, 2008. This season will add six new recurring regulars, played by Grant Bowler, Mark Consuelos, Heather Tom, Val Emmich, and Ralph Macchio. Linsday Lohan, Julian De La Celle, Derek Riddell and Eddie Cibrian return from the second season for more appearances, while Romijn, Rodiguez and Gorham will make their final bows during this cycle. "The Show" by Australian singer Lenka is used as the promo theme for the season.

For this season, Betty decides to move on from Henry and Gio, and after a cross-country trip around the United States, decides to move out of Casa Suarez and into an apartment of her own, hoping that this will help her advance in her quest to move up in the publishing business. Betty also attracts the interest of a musician named Jesse who is living in the apartment across from hers. In addition, she buries the hatchet with Kimberly "Kimmie" Keegan, her childhood nemesis and manager of Flushing Burger, where Ignacio works.

In the meantime, Daniel is demoted to Editor-in-Chief of Player magazine, after Alexis decided to bring back Wilhelmina as Editor-in-Chief. Daniel takes the decision to fight for custody of his son Daniel Jr., and for his Job at Mode;which he takes back from Wilhelmina.

Wilhelmina's sudden rise to the top, means that she lures Betty into her world - by offering her the job of her assistant- in her attempt to mold her. Of course, this doesn't last and when Betty helps Daniel get his job back, she becomes his assistant again.

Marc's romance with Cliff continues and his jealousy over being passed over by Wilhelmina, when she lured Betty back to Mode, became a move that prompted Marc to set the downfall in motion for his boss, allowing him to get his job back.

Claire's stepping in to stop Wilhelmina from using the family and also to get Hot Flash ready.

Hilda is continuing to see Tony, who is still married, but when Ignacio finds out, will the relationship last? Unfortunately, thanks to his wife, Hilda breaks it off after she talk to her after the woman mistaked her for the "other woman [Betty]." Meanwhile, Justin is getting ready to break into show business in Broadway, in what is said to be a "musical episode".

Amanda continues the quest to find her father and also moves in with Betty when her spending spirals out of control.

Christina is dealing with Stuart's drug problems and her pregnancy with the unborn Meade baby, which in turn would take a turn for the worse after she is pushed down a flight of stairs. Daniel is framed for it and Betty decides to prove he is wrong.

After using some help from Marc and Amanda, they find out Daniel's sister did it. Alexis turns herself in afterwards. While in jail, Alexis reveals to Daniel that a paternity test for Daniel Jr. revealed that Daniel is not the father. Alexis is the father, since she slept with DJ's mother back when she was a man. As a result of the revelation, Daniel Jr's grandparents get custody of the boy.

In the meantime, Wilhelmina puts pressure on Alexis to give up her entire control of the Meade company, in exchange for Wilhelmina's help in getting Alexis' charges dropped. In the end, a compromise is reached, and control of the company is divided equally between Wilhelmina and Daniel. The two become co-owners and co-editors of the publishing empire. This means Wilhelmina only has 50% to go until she controls the whole empire by herself.

On November 4, 2008, TV Guide reported that Nikki Blonsky is due to make a guest appearance on an upcoming episode. Blonsky will play an assistant at Elle, the rival magazine of Mode.