Siragusa was an undrafted free agent in 1990 and was signed by the Indianapolis Colts as a defensive tackle. He used to play nose tackle to draw the double teams when the Indianapolis Colts were in a 3-4 defense or 4-3 defense. As a rookie, he appeared in 13 games, started six games, and recorded one sack, 36 total tackles, and one fumble recovery. In the 1991 season, he appeared in 13 games, started six, and recorded two sacks, one fumble recovery, and 46 combined tackles. In the 1992 season, he appeared in all 16 games, started 12, and recorded three sacks and 65 combined tackles. In the 1993 season, he appeared in and started 14 games and recorded 1.5 sacks and 76 combined tackles. In the 1994 season, he appeared in and started all 16 games and recorded five sacks, 88 combined tackles, two forced fumbles, and one fumble recovery. In the 1995 season, he appeared in and started 14 games and recorded two sacks, 49 total tackles, and one forced fumble. While Siragusa was a key part of the 1995 team that was one Hail Mary pass away from reaching Super Bowl XXX, he was enraged when Colts coach Ted Marchibroda was given a no-raise, no-extension contract offer that he rejected before resigning, and Siragusa was open about his dislike for new coach Lindy Infante and the team’s Vice President of Football Operations Bill Tobin. In the 1996 season, he appeared in and started ten games and recorded two sacks, 45 combined tackles, and one fumble recovery.

Siragusa married his wife, Kathy, on April 22, 1995. The two have three children, Samantha, Ava, and Anthony Jr. They currently reside in Florham Park, New Jersey.

In 1997, Siragusa signed with the Baltimore Ravens. In the 1997 season, he appeared in 14 games, started 13, and recorded one fumble recovery and 27 total tackles. In the 1998 season, he appeared in and started 15 games, and recorded one forced fumble, one fumble recovery, and 41 total tackles. In the 1999 season, he appeared in and started 14 games, and recorded two forced fumbles, one fumble recovery, 3.5 sacks, and 36 total tackles. He was a part of the 2000 Baltimore Ravens defense that allowed the fewest total points in NFL history for a 16-game season. In the 2000 season, he appeared in and started 15 games, and recorded one fumble recovery and 27 total tackles. Siragusa was fined $10,000 for an illegal hit on Oakland Raiders quarterback Rich Gannon in the 2000 AFC title game, injuring Gannon’s shoulder. 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, where he had two sacks and 28 total tackles. 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 also played a Russian mobster in the 2002 movie 25th Hour.

Out of a concern for men with prostate cancer, in 2013 Siragusa began appearing in an ad campaign for Depend for Men, saying, “I decided to go and shoot the commercial and bring a little bit of lightness to [the problem] where guys can talk about it and after I did the commercial you wouldn’t believe the response.”

Siragusa was a sideline reporter and analyst during NFL games on the Fox Network until his firing following the 2015 NFL season. Siragusa usually appeared with Kenny Albert (before Albert, Dick Stockton and Curt Menefee) and Daryl Johnston. In 2015, he was paired with Thom Brennaman and Charles Davis. He 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 Tiff’s. The original name of the franchise was Tiffany’s, but after a lawsuit by Tiffany & Co., the luxury jeweler, the name was shortened. He hosts Man Caves on the DIY network. He also presents a documentary program called Megamachines on the Discovery Channel.

Siragusa has made a few appearances at his alma mater, the University of Pittsburgh. He was one of several honorary captains during the renewal of the Penn State–Pittsburgh football rivalry in 2016, shortly after ending his stint with Fox.