In 1962, following an innovative AFL trend of drafting players from small colleges, the Bills drafted Sestak as a tight end in the 17th round from McNeese State University. Sestak would never play that position for the Bills, but instead became one of the league's greatest defensive tackles. At 6-4, he had the size, speed and strength to handle any offensive lineman.
Sestak was a starter in his rookie year and, until a series of knee injuries ended his career after the 1967 season, used his strength to dominate the line of scrimmage. Sestak was a three-time selection to All-American Football League teams and a unanimous All-AFL defensive tackle in three consecutive years; 1963, 1964 and 1965. Sestak served as the cornerstone of a defense that took the Bills to the playoffs four straight years (1963–1966) and consecutive AFL championships in 1964 and 1965. Over the 1964 and 1965 seasons, Sestak and his defense mates held opposing rushers without a touchdown for seventeen consecutive games, a Professional Football record that still stands. Twice during his outstanding career he realized the defensive lineman's "dream", returning interceptions for touchdowns, and once returned a recovered fumble for a score.
His teammates described his play as "crazy as hell".
During the 1960s, only six professional defensive linemen were unanimous All-League selections for three or more years, Sestak (3), Bob Lily (5), Merlin Olsen (4), Willie Davis (3), Gino Marchetti (3), and Deacon Jones (3). The latter five, all former NFL players, have already been inducted into the Pro Football Hall of Fame, while Sestak, a star from the AFL, like many other AFL players has been ignored by the Hall of Fame selectors.
In January 1970, Sestak was selected as a member of the All-Time All-AFL Team, and in 2009 as a member of the Bills' 50th Anniversary Team. In 2007, Tom Sestak was inducted into the National Polish American Sports Hall of Fame.