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.