Majorino, an Italian American, was born in Westlake, California, the daughter of Sarah (née Black) and Robert "Bob" Majorino, who is a real estate agent. She has an older brother, Kevin.

Majorino began her acting career in a 1992 sitcom called Camp Wilder. Her first film role was 1994's When a Man Loves a Woman. She subsequently starred in the leading roles of the family films Corrina, Corrina and Andre, both of which were released in August 1994. Her next film was the 1995 action film Waterworld, playing a child rescued by Kevin Costner's character, The Mariner.

Most of her roles throughout the late 1990s were in independent films or made-for-television productions; she played the title role in the 1999 television film, Alice in Wonderland. After Alice, Majorino took time off from the business.She did not appear in another film until 2004, when she starred opposite Jon Heder in the movie Napoleon Dynamite. From 2004 onward, she played a recurring role on UPN's series, Veronica Mars, as the computer-savvy Cindy “Mac” Mackenzie. Show creator Rob Thomas created the role with her in mind. Majorino had met Thomas while interviewing him for a report on one of his books. Majorino became a series regular in the third season, prior to the series cancellation. At present, she has a recurring role on the cable television series Big Love.

Majorino has appeared in the music video for "Blind" by rock group Lifehouse. She has also formed a rock band called "The AM Project" with her brother Kevin.