Palillo played goofball Horshack on the ABC series from 1975 to 1979 alongside Gabe Kaplan and a young John Travolta. Horshack's trademark was raising his hand excitedly in class and saying, "Ooh ooh ooooh!" when he thought he knew the answer to one of Mr. Kotter's questions.
After Kotter, Palillo did a lot of voice acting and played the multicolored talking puzzle box in the trippy animated series Rubik, the Amazing Cube. He also taught at the G-Star School of the Arts.