Drescher was born in Flushing, Queens, New York City, to an Ashkenazi Jewish family of Eastern Europe origin (her great-grandmother was born in Focsani, Romania).She grew up in Kew Gardens Hills, Queens with her parents Sylvia and Morty Drescher and was a studious girl who was popular in school. Drescher attended Hillcrest High School in Jamaica, Queens, where she met her future husband, Peter Marc Jacobson, eventually marrying him in 1978, at age 21.

Her first break was a bit part in the movie Saturday Night Fever (1977).

Drescher continued to play small but memorable roles in movies, until she and her husband finally created her own television show, The Nanny in 1993. She was visiting her friend, model Twiggy, in England and came up with the plotline. The show aired on CBS from 1993 to 1999, becoming an instant success, and Drescher became an instant star. In this sitcom, she played a charming and bubbly woman named Fran Fine who casually became the pantyhose-clad nanny of three children; with her wit and her charm, she endeared herself to their widower father Maxwell Sheffield, a stuffy, composed, proper British gentleman and a Broadway producer (played by British actor Charles Shaughnessy).

Drescher's voice is a combination of a high nasal pitch and a Queens, New York accent that people find either annoying, endearing, or humorous (or all three). In her autobiography, Drescher discusses the fact that this is her real voice — even though it is played up a little on-camera — and discusses the many voice lessons she had to take to overcome it for movie auditions, only to have it, and her machine-gun titter, end up being her trademark. Her first book is appropriately and humorously titled Enter Whining.

Fran has also appeared in a number of films, including Hollywood Knights (1980), This Is Spinal Tap (1984), UHF (1989) starring "Weird Al" Yankovic, Jack (1996), directed by Francis Ford Coppola, The Beautician and the Beast (1997) (for which she was also executive producer) and Picking Up the Pieces (2000) co-starring Woody Allen. In 2007 Fran announced she would voice the character of Pearl in the animated movie Shark Bait.

Drescher married her highschool sweetheart, Peter Marc Jacobson. Jacobson was Drescher's constant supporter in her show-business career, and he wrote, directed, and produced her signature television series, The Nanny. They divorced in 1999.

In January 1985, robbers ransacked Drescher's and Jacobson's Los Angeles apartment and raped her and a friend at gunpoint. It took her many years to overcome this ordeal, and it took her even longer to admit this to the press. She was paraphrased as saying in an interview with Larry King that although it was a traumatic experience, she found ways to turn it into something positive. In her book Cancer Schmancer, the actress writes: "My whole life has been about changing negatives into positives." She saw her rapist sent to prison.

After separating in 1996, Fran (who never had children) divorced her husband, Peter Marc Jacobson, in 1999. She then dated a man sixteen years her junior from 1998–2002. Her beloved dog, Chester, who made many appearances in her movies and on The Nanny, died in 2000 at age eighteen. She now has a chocolate Pomeranian named Esther and lives in New York.

Drescher was admitted to Los Angeles's Cedars Sinai Hospital on June 21, 2000, after doctors diagnosed her with uterine cancer. But emergency surgery caught it early as it was only at Stage 1 and she didn't have to undergo chemotherapy. She has been given a clean bill of health and no post-operative treatment has been ordered. She wrote about her experiences in her second book, Cancer Schmancer.

On June 21, 2007, the day which marks her 7th anniversary of wellness, Drescher announced the national launch of the Cancer Schmancer Movement, a non-profit organization dedicated to ensuring that all women's cancers be diagnosed while in Stage 1, the most curable stage.

Fran says "we need to take control of our bodies, become greater partners with our physicians and galvanize as one to let our legislators know that the collective female vote is louder and more powerful than that of the richest corporate lobbyists." Her goal is to live in a time when women's mortality rates drop as their healthcare improves and early cancer detection increases. More information can be found on her website at cancerschmancer.org.

In recent years, Drescher has made a return to television both with leading and guest roles. In 2005, she returned to TV with the sitcom Living with Fran, in which she played Fran Reeves, a middle-aged mother of two, living with Riley Martin (Ryan McPartlin, Passions), a guy half her age and not much older than her son. Former Nanny costar Charles Shaughnessy appears as her philandering ex-husband, Ted. Living with Fran was cancelled May 17, 2006, after two seasons.

In 2003, Drescher appeared in episodes of the short lived sitcom, Good Morning, Miami as Roberta Diaz.

In 2006, Drescher guest starred in an episode of Law & Order: Criminal Intent; the episode, "The War at Home", aired on US television on November 14, 2006. In the same year, she also gave her voice to the role of the female golem in The Simpsons episode "Treehouse of Horror XVII". In 2007, Drescher appeared in the US version of the Australian improvisational comedy series Thank God You're Here. The program was cancelled after eight episodes.

On February 23, 2008, on Rosie O'Donnell's video blog it was announced that Rosie and Fran would be doing a "fun, happy, family comedy" together. It is said to be called 'The New 30'.

On February 29, 2008, Fran went on Larry King Live to discuss the Obama/Clinton primary.

On June 17, 2008, Fran went on "Chelsea Lately" and discussed many different topics.

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