Her debut role was in the sitcom Valerie in 1987, in which she played "Pamela", the niece of Mrs. Poole. Sweetin also provided the voice of "Sally Brown" in It's Christmastime Again, Charlie Brown. Jeff Franklin cast her as "Stephanie Tanner" in Full House in 1987 and she was on the show until its end in 1995. After the show's finale, Sweetin finished high school and attended Chapman University in Orange, California.

She returned to television by hosting the second season of the Fuse TV show Pants-Off Dance-Off. Sweetin starred in a TV pilot, Small Bits of Happiness, a dark comedy centered around a suicide prevention specialist; it won Best Comedy at the 3rd Annual Independent Television Festival, in Los Angeles.

At age 20, Sweetin married Los Angeles Police Officer Shaun Holguin. Fellow Full House castmate Candace Cameron served as her matron of honor, with Cameron's daughter, Natasha, serving as a flower girl. Sweetin and Holguin divorced in 2006.

Sweetin met Cody Herpin, a film transportation coordinator, through friends, and they started dating in May 2007. After just two months of dating, they wed in Las Vegas on July 14, 2007. The couple has one daughter named Zoie Laurelmae who was born on April 12, 2008.

On Wednesday, November 19, 2008, Sweetin filed for legal separation from Cody Herpin. A representative of Sweetin told Life & Style that "She felt this was the way she had to go." On Tuesday, April 20, 2010, the divorce was finalized.

Sweetin wrote a memoir which is under contract with Spotlight Entertainment and chronicles her downward spiral of alcohol and drug abuse that began with the ending of Full House. The book, titled unSweetined, was released in bookstores November 3, 2009.

On April 30, 2010, Sweetin's rep confirmed that she and her boyfriend of one year, Morty Coyle, are expecting a child later this year.