Nicknamed "Goose," Siragusa signed with the Indianapolis Colts in 1990 as an undrafted free agent. He remained with the team through the 1996 season.

In 1997, Siragusa signed with the Baltimore Ravens. He was a key part of the 2000 Baltimore Ravens defense that allowed the fewest total points in NFL regular season history. He helped lead the Ravens to their first Super Bowl in franchise history in Super Bowl XXXV where they beat the New York Giants 34-7.

Siragusa retired following the 2001 season. He finished his career with 562 tackles (416 solo), 22 sacks, five forced fumbles, nine fumble recoveries for 12 yards, and 28 pass deflections in 170 career games.

Siragusa has been sideline reporter during NFL games on the Fox Network. He has also appeared as the character Frankie Cortese in the HBO hit series The Sopranos. He partnered up with Michael Romanelli and opened a restaurant chain called Tiffany's (Tifs). He also has hosted "Man Caves" on the DIY network and has presented a documentary program called Megamachines.