Siragusa also played a Ukrainian mobster in the movie 25th Hour.

Siragusa attended David Brearley High School in Kenilworth, New Jersey. In high school, he played football and was also a member of the wrestling team. He was the New Jersey state wrestling champion with a 97-1 career record. In football, he played defensive line, punted and place kicked. He had a 39-yard punting average and was 15-18 on PATs. Upon completion of high school, Siragusa attended the University of Pittsburgh where he was a member of the football program from 1986 through 1989.

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. 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 VP of Football Operations Bill Tobin.

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

In 1997, Siragusa signed with the Baltimore Ravens. He was a part of the 2000 Baltimore Ravens defense that allowed the fewest total points in NFL history for a 16-game season.

Siragusa was fined $10,000 for an illegal hit on Oakland Raiders QB 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. 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.

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 and is the spokesperson for an adult diaper in a national advertising campaign.