LaPaglia's credits include the films Innocent Blood, The Client, Looking for Alibrandi, Lantana, Summer of Sam, So I Married an Axe Murderer, and Empire Records. LaPaglia also appeared in nine episodes of the sitcom Frasier, including the series finale, playing Daphne Moon's brother Simon. The role won him an Emmy Award for Outstanding Guest Actor in a Comedy Series. He also appeared uncredited in the film Analyze That playing an actor, Anthony Bella, who appeared in the TV show-within-a-film Little Caesar. LaPaglia also played the role of Jimmy Wyler, the lead during the second and final season of the television program Murder One.

LaPaglia appeared in the Australian political thriller Balibo, about the killing of the five Australian journalists in the town of the same name in East Timor in 1975. LaPaglia played the part of Roger East, another Australian journalist, who went to investigate the deaths of the newsmen, only to be killed the day after the Indonesian invasion.

In 2002, LaPaglia co-starred as a fire captain opposite Sigourney Weaver in the The Guys, a film about New York firemen who died in the World Trade Center. He also played the role onstage, rotating with Bill Murray and others. “We did it as a tribute to the men,” said LaPaglia. “I’ve been so lucky to do it, to be part of this experience. But I can’t go back to that morning or watch the video. It’s too painful."

In addition to leading the cast of Without a Trace, LaPaglia co-wrote an episode titled "Deep Water" with Byron Belasco, the show's usual writer.