She returned several years later in what would become one of her best known roles, the character Deb in the 2004 film Napoleon Dynamite. Since her return to acting, Majorino has also starred in television series such as Veronica Mars and Big Love.

Majorino began her acting career in a 1992 sitcom called Camp Wilder. Her first film role was in 1994's When a Man Loves a Woman. She subsequently starred in leading roles in 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 named Enola, who is rescued by Kevin Costner's character, The Mariner.

She played the title role in the 1999 television film, Alice in Wonderland. After Alice, Majorino took time off from the business. She has since cited burnout as the reason for her hiatus from acting. Majorino did not appear in another film until 2004's cult film 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 show's third and final season. During her time on Veronica Mars she also started appearing in a recurring role on the cable television series Big Love with Waterworld costar Jeanne Tripplehorn and fellow Veronica Mars cast members Amanda Seyfried and Kyle Gallner.

In 2009, she started filming The Deep End, a new television show for ABC. The show was canceled after only six episodes were aired.

Majorino, of Italian descent, was born in Westlake, California to Sarah (née Black) and real estate agent Robert "Bob" Majorino. She has an older brother, Kevin, with whom she has formed a rock band, The AM Project. Majorino has also appeared in the music video for the song "Blind" by rock group Lifehouse.