Chosen in the fourth round (25th overall) of the 1964 AFL Draft out of Boston University, Butch Byrd arrived in Western New York as an explosive, physical athlete. Stepping straight into the starting lineup as a rookie, Byrd locked down the right cornerback spot and quickly established himself as the premier ball-hawking defensive back in the American Football League.

Byrd uniquely combined sprinter's quickness with the physical strength typical of a 1960s cornerback. Playing on the island in Lou Saban's defense, he was adept at reading quarterbacks’ eyes, intercepting boundary routes, and breaking up deep passes. When he gained possession, his experience as a college running back quickly became evident—transforming interceptions and punt returns into pivotal scores with his open-field running ability.

Byrd made a notable impact in his rookie 1964 season, intercepting seven passes and returning one for 72 yards and a touchdown. He also recorded another interception in the postseason, contributing to Buffalo's 20–7 win over San Diego in the AFL Championship. His dominance reached its peak during Buffalo's 1965 title defense, where he snagged five interceptions while also returning punts. Byrd was named First-Team All-AFL and earned his second of five AFL All-Star selections as the Bills secured back-to-back AFL Championships.

Byrd was a relentless big-play threat in the late 1960s. In 1966, he intercepted six passes and returned a 74-yard punt for a touchdown in the AFL Championship Game. He received First-Team All-AFL honors in 1966 and 1969, and Second-Team All-AFL awards in 1964 and 1968. Over seven seasons with Buffalo, he started 98 straight regular-season games without missing any.

After the 1970 season, the Bills traded Byrd to Denver, where he played one final year in 1971 before retiring. His career excellence was recognized by the Pro Football Hall of Fame when he was named to the AFL All-Time Second Team.

In Western New York, Byrd played in 98 regular-season games, leaving as the undisputed single-season and career king of the Bills' secondary. Over half a century later, he remains Buffalo's all-time franchise leader in interceptions (40), interception return yards (666), and interception return touchdowns (5).