His best known role was as David Healy (first introduced as Kevin Healy) in the U.S. sitcom Roseanne. His character was the artistically-talented, curly-haired, soft-spoken boyfriend (later husband) of Darlene, the droll, tomboyish second daughter of the Conner family played by Sara Gilbert. Galecki was cast in similar roles in the 1997 summer slasher, I Know What You Did Last Summer as a jealous loser who has an eye for Jennifer Love Hewitt, and the 1998 dark comedy The Opposite of Sex as a gay teen who lies about being molested. In 1989, he played Russell "Rusty" Griswold in National Lampoon's Christmas Vacation. In the year 2000, Galecki took a bit of a twist and reunited with the same filmmaker, who cast him in Bounce as another gay man, an assistant to Ben Affleck's character Buddy Amaral, who also helps Dodge out with his love life.
Galecki continued his film streak with other David Healy-like roles in Suicide Kings as a nebbishy rich kid who folds easily under pressure, and brief bit parts in high-profile films like Bean as a bad-boyfriend biker, and a minor supporting part in Vanilla Sky. Galecki showed that he had range as an actor with typecast-breaking roles like a young criminal delinquent in A Family Torn Apart, a TV movie based on a true story about a serial murderer and the death of a pair of parents.
He also played the half-brother of the main characters, sisters Hope Shanowski and Faith Fairfield, in the TV Sitcom Hope & Faith. Galecki also appeared as a guest star in a first season episode of My Name Is Earl, and as a character named "Trouty" on TBS's sitcom, My Boys.
Galecki starred fall/winter 2006-07 in the Broadway play The Little Dog Laughed as Alex, a male prostitute. In this role, he was required to do a full-frontal nude scene, the first of his acting career. Galecki originated the role earlier in 2006 at Second Stage Theatre. The widely popular comedy by Douglas Carter Beane had a successful run at Second Stage and moved to the Cort Theatre. The play closed on February 18, 2007.
Galecki currently stars as Leonard Hofstadter, PhD on a new CBS show, The Big Bang Theory, which debuted September 24, 2007. He also appears in the music video for the Dave Matthews Band song "Satellite".