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".