His acting debut came in the 1987 CBS miniseries Murder Ordained with JoBeth Williams and future Roseanne co-star John Goodman. Then 1989, he played Russell "Rusty" Griswold in National Lampoon's Christmas Vacation. His best known early role, though, 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. Johnny Galecki was cast 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 the year 2000, Johnny Galecki reunited with the same filmmaker who cast him in Bounce as Seth (a gay man), an assistant to Ben Affleck's character Buddy Amaral, who helps Amaral out with his love life.
Johnny Galecki continued his film streak with roles in Suicide Kings as a nebbishy rich kid who folds easily under pressure and brief bit parts in high-profile films such as Bean as a bad-boyfriend biker and a minor supporting part in Vanilla Sky. Johnny Galecki showed that he had range as an actor with 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.
Johnny Galecki appeared in a first-season episode of My Name Is Earl as a golfer. Without his knowledge, Earl and Randy improve his golf score by making it appear that he got numerous holes-in-one, taking advantage of a custom that a player scoring a hole-in-one must buy a round of drinks. His obsession with improving his golf game without Earl and Randy's assistance destroys his life — he loses his job and girlfriend and is forced to live out of his car.
He played a character named Trouty on TBS's sitcom My Boys. He also played the half-brother of the main characters, sisters Hope Shanowski and Faith Fairfield, in the TV sitcom Hope And Faith. In late 2006/early 2007, Johnny Galecki starred 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. "At its core, the play is about what we all sacrifice to be successful, whatever our careers or goals," he explains. Johnny Galecki originated the role earlier in 2006 at Second Stage Theater. 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, with Johnny Galecki taking home a 2007 Theater World Award for his performance.
Johnny Galecki currently stars as Leonard Hofstadter, Ph.D, on the CBS sitcom The Big Bang Theory, which debuted September 24, 2007. Sara Gilbert, who played his girlfriend and later his wife in Roseanne, has appeared as a recurring character. Johnny Galecki is a cellist and, as Leonard Hofstadter, has played celle on the show.
Johnny Galecki appeared briefly in the 2008 superhero comedy Hancock, alongside Will Smith and Jason Bateman. He also appears in the music video of the Dave Matthews Band song "Satellite".
In May 2010 Johnny Galecki appeared at the Logies in Australia.
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