Drafted in the second round (29th overall) of the 1980 NFL Draft out of Auburn—where he was a First-Team All-SEC selection—Joe Cribbs arrived in Western New York as an instant offensive focal point. Functioning as a dual-threat weapon out of the backfield, Cribbs gave Buffalo a dynamic dual-threat running back who could slice through interior defensive lines or swing out wide as a lethal pass-catcher.

Cribbs relied on rapid lateral vision, smooth cutback agility, and soft hands out of the backfield. Equally dangerous between the tackles and in open space, he excelled at reading blocking schemes, pressing the hole, and accelerating into the secondary. As a receiver, Cribbs posed a mismatch for linebackers, running sharp wheel and angle routes that allowed him to turn short dump-off passes into massive gains downfield.

Cribbs made an immediate statement during his 1980 rookie campaign, rushing for 1,185 yards and 11 touchdowns while adding 52 receptions for 415 yards. Despite leading the league with 16 fumbles, his 1,600 yards from scrimmage helped lead Buffalo back to the playoffs and earned him UPI AFC Rookie of the Year honors alongside his first Pro Bowl selection.

Cribbs significantly improved his ball security while maintaining his elite production over the next three seasons. In 1981, he turned in 1,700 total scrimmage yards (1,097 rushing, 603 receiving) and 10 total touchdowns to earn his second Pro Bowl nod. After a strike-shortened 1982 season where he still rushed for 633 yards in just seven games, Cribbs returned to peak form in 1983, tallying 1,131 rushing yards and 57 receptions for 524 receiving yards to secure his third Pro Bowl selection. In each of his three Pro Bowl seasons, Cribbs ranked among the top 10 in the NFL in yards from scrimmage.

Seeking better compensation, Cribbs signed a contract with the USFL's Birmingham Stallions in 1983, jumping leagues to play the 1984 and 1985 USFL spring seasons. Following the resolution of legal disputes, he returned to the Bills in the fall of 1985, appearing in 10 games (399 rushing yards). Prior to the 1986 season, the Bills traded Cribbs' NFL rights to the San Francisco 49ers, bringing his time in Western New York to an official close.

With the Bills (1980–1983, 1985), Cribbs played in 64 regular-season games, accumulated 4,445 rushing yards, 1,783 receiving yards, 6,228 yards from scrimmage, and 36 total touchdowns.