Galecki made his acting debut in the 1987 CBS miniseries Murder Ordained with JoBeth Williams and future Roseanne co-star John Goodman. In 1989, Galecki portrayed Rusty Griswold in National Lampoon’s Christmas Vacation. In 1990, he was cast as Danny Nash, the son of Robert Urich’s lead character, on the NBC comedy American Dreamer; the following season, he was a regular cast member on the ABC sitcom Billy, a spin-off from Head of the Class. He appeared in one episode of Blossom in 1991, opposite his future The Big Bang Theory co-star Mayim Bialik. He played a young delinquent in A Family Torn Apart, a 1993 TV movie based on a true story about a serial killer.

Galecki also appeared in the 1995 music video for the Dave Matthews Band song “Satellite”.

During his run on Billy, Galecki began making guest appearances on the hit ABC sitcom Roseanne as the younger brother of Mark Healy (Glenn Quinn), who began a relationship with Darlene Conner (Sara Gilbert). Introduced in his first appearance as Kevin Healy, his name was soon changed to David. After a few more guest shots, Galecki was named a permanent Roseanne cast member from the fall of 1992 onward, after the cancellation of Billy. He would remain in the role of David Healy until the end of Roseanne’s run in 1997, with the character eventually marrying Darlene and fathering two children with her. Galecki’s character on The Big Bang Theory would also have a short-lived relationship with Gilbert’s character on the same show.

After Roseanne ended, Galecki had small roles in a string of films, including the 1997 summer slasher film I Know What You Did Last Summer (as the killer’s first victim), Bean (1997), The Opposite of Sex (1998), Bounce (2000) and Vanilla Sky (2001). He had larger roles in the 1997 film Suicide Kings and the 2003 film Bookies, a comedy thriller film about four college students. Galecki appeared as a golfer in a 2005 episode of My Name Is Earl entitled “Stole Beer from a Golfer”.

In 2005, Galecki played Mark Corrigan in a pilot for a US adaptation of the British sitcom Peep Show. He played a character named Trouty on TBS’s sitcom My Boys, and the half-brother of the main characters, sisters Hope Shanowski and Faith Fairfield, in the sitcom Hope & Faith. Galecki originated the role of Alex, a male prostitute, in the play The Little Dog Laughed by Douglas Carter Beane, in 2006 at Second Stage Theater. He stayed in the role for the play’s Broadway run at the Cort Theatre in late 2006 and early 2007. Galecki said at the time, “At its core, the play is about what we all sacrifice to be successful, whatever our careers or goals.” The play was a commercial and critical success, and Galecki won a 2007 Theater World Award for his performance.

Galecki appeared briefly in the 2008 superhero comedy Hancock, alongside Will Smith and Jason Bateman. In July 2011, he played a parody version of himself in three episodes of Entourage. He also appeared in the film In Time (2011) with Justin Timberlake and Amanda Seyfried.

Galecki appeared in one episode of the 2018 revival of Roseanne on ABC. The show, despite its high ratings, was cancelled after Roseanne Barr posted a racist tweet about Valerie Jarrett. Roseanne was replaced by a new program, The Conners, which premiered in October 2018 and featured the same cast without Barr. Galecki has occasionally appeared as David on The Conners.

In August 2018, Galecki started dating Alaina Meyer. On May 3, 2019, Galecki and Meyer announced that they were expecting their first child together. Their son, Avery, was born in December 2019.