Selected in the fourth round (86th overall) of the 1985 NFL Draft out of Division II Kutztown University, Andre Reed arrived in Buffalo as a small-school prospect with raw athletic upside. He quickly shattered expectations, spending 15 seasons as Jim Kelly's most dependable target and establishing himself as one of the most prolific wide receivers in NFL history.

Reed revolutionized slot and intermediate receiver roles within Marv Levy's fast-paced "K-Gun" offense. Known for his fearless approach to the middle of the field, he specialized in running slants, shallow crosses, and seam routes through dense secondary coverage. Once he caught the ball, Reed became a strong runner, leveraging his powerful lower body and quick bursts of speed to make significant yardage after the catch (YAC).

Reed made an impressive rookie debut in 1985 with 48 catches, 637 yards, and four touchdowns. In 1986, he became Buffalo's top receiver, leading in both receptions and yards. His rise to elite status aligned with Buffalo's no-huddle offense. Reed received his first of seven straight Pro Bowl selections (1988–1994) in 1988, with 71 catches for 968 yards. He hit his career high in receiving yards in 1989, with 88 catches, 1,312 yards, and nine touchdowns, earning Second-Team All-Pro honors.

During Buffalo's four straight AFC championship runs, Reed was the offense's key player in crucial moments. In 1991, he made 81 catches for 1,113 yards and scored 10 touchdowns, setting a personal best, with another impressive season in 1992. His postseason performance in 1992 solidified his reputation in big games, especially during "The Comeback" against the Houston Oilers, where he caught eight passes for 136 yards and scored three second-half touchdowns, helping set the NFL record for the biggest playoff comeback.

Reed enjoyed another prolific season in 1994, setting a single-season career high with 90 receptions for 1,303 yards. Despite a hamstring injury in 1995, he bounced back in 1996 with 66 catches for 1,036 yards—his fourth 1,000-yard campaign. He remained a steady starter through his final year in Buffalo in 1999, then concluded his career with Washington in 2000.

Over 15 seasons with Buffalo, Reed established franchise records that remain unbroken: 941 receptions, 13,095 receiving yards, and 86 receiving touchdowns in 221 regular-season games. Upon retiring, he ranked just behind Jerry Rice in career postseason receptions (85) and Super Bowl catches (27). The franchise enshrined Reed on the Buffalo Bills Wall of Fame in 2006. Eight years later, he took his place in the Pro Football Hall of Fame in 2014.