Anthony LaPaglia was born in Adelaide, South Australia, the son of Maria, a secretary, and Eddie LaPaglia, an auto mechanic and car dealer. He is of Italian and Dutch extraction. He is the brother of Jonathan Lapagliaanother movie-actor. His other brother, Michael, is a car wholesaler in Los Angeles.

LaPaglia first began his venture into the world of dramatic art in his late teens. He enrolled at the "South Australian Castings Agency", more commonly referred to as "S.A. Castings". Rather than completing the two and half year course offered by "S.A. Castings", Anthony completed one and half years of the course, then left Adelaide and headed to Los Angeles.

LaPaglia is best known for his role as FBI agent Jack Malone on the American TV series Without a Trace, a role which won him a Golden Globe Award. His credits also 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 on nine episodes of the sitcom Frasier, including the series finale, as 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. He also played the role of Jimmy Wyler, the lead during the second and final season of the television program Murder One.

In September 2007, it was announced that LaPaglia would be appearing 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 will play 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.