Bernsen's first nation-wide attention came from two-year role on the soap opera, Ryan's Hope. He was propelled into stardom when he was cast as one of the stars on the hit primetime Steven Bochco series L.A. Law. The role earned him Emmy and Golden Globe nominations, appearances on dozens of magazine covers, and guest starring roles on then-popular shows such as Seinfeld and The Larry Sanders Show. He was one of the few actors to remain on the show from 1986 until the show's end in 1994. While portraying Roger Dorn in the feature film Major League, Bersen was involved in a real life altercation with co-star Charlie Sheen. During the scuffle, Bersen suffered a slight tear in his rotator cuff, leaving him unable to throw a baseball. For this reason, Bersen was not in any on-field baseball action for the sequels Major League II and Major League: Back to the Minors.

Bernsen appeared on General Hospital when he played the recurring role of attorney John Durant from September 2004 u