In the 1985 NFL Draft, Reed was drafted by the Buffalo Bills in the fourth round with the 86th overall selection, making him just the second player ever from Kutztown to be selected in an NFL draft (the first being Don Shaver in 1981). He played for the Bills for 15 consecutive seasons, from 1985 through 1999, during which he played in four Super Bowls for the Bills. He was released in the 2000 offseason, along with fellow longtime Bills Thurman Thomas and Bruce Smith, after the team found itself in severe salary cap trouble; the roster dump began a period of downfall from which the Buffalo Bills did not reach the playoffs until the 2017 season.

Following the Bills’ victory against the Oilers, Reed went on to catch eight passes for 152 yards in the Bills’ 52–17 Super Bowl XXVII loss, on January 31, 1993, to the Dallas Cowboys.

Reed set season career highs with 90 receptions in 1994, ten touchdowns in 1991, and 1,312 receiving yards in 1989.

Reed is mentioned in the 1996 film Jerry Maguire as one of several NFL wide receivers with lucrative contracts, as Rod Tidwell, a fictional wide receiver for the Arizona Cardinals, played by Cuba Gooding, Jr., tells his agent, played by Tom Cruise, that his contract warrants high pay.

In 2000, Reed signed a two-year contract with the Denver Broncos in June but was buried on the depth chart behind Rod Smith, Ed McCaffrey, Robert Brooks and Travis McGriff. Reed eventually asked for his release from the Broncos after then Broncos Head Coach Mike Shanahan informed Reed that he would be inactive for their 2000 season opener and wanted to make a more immediate contribution. He eventually joined the Washington Redskins and retired after the 2000 season.

Since his NFL retirement in 2000, Reed has provided football commentary on the ESPN2 show, First Take, and appears periodically as a football analyst on NFL on Fox. He has also appeared on the Spike TV sports series Pros vs. Joes in the show’s second season.

Reed became eligible for induction into the NFL’s Pro Football Hall of Fame, the highest honor afforded a former NFL player, in 2006. However, he was not selected for induction in any of his first four years of eligibility, due in part to the logjam of accomplished wide receiver candidates, including Art Monk, Michael Irvin, and Cris Carter. Although Irvin, Monk and Carter are now enshrined as of 2007, 2008 and 2013 respectively, the logjam became worse than ever for Reed as he was once again overlooked in 2009, and 2010, which saw wide receiver candidates Jerry Rice and Tim Brown both eligible for the first time. Rice has long been considered one of the greatest players in league history and was almost assured of being a first ballot Hall of Famer, making 2010 a long shot for Reed. As expected, Rice was inducted, which did clear some of the logjam going forward for Reed.

In 2006, Reed was voted into the Buffalo Bills Wall of Fame, joining a number of other players from Bills history whose names are enshrined in the field-encircling cement of Buffalo’s New Era Field.

The 2009 induction ceremony was overwhelmingly pro-Buffalo Bills because former teammate Bruce Smith and owner Ralph Wilson were both inducted. Through the night, Reed was referred to multiple times as “future Hall of Famer” with various speeches voicing their ringing endorsement for Reed as a candidate.

The Andre Reed Foundation was established in 2010 to help underprivileged children reach their full potential and become responsible contributors to their communities. Reed is currently a Boys & Girls Clubs of America (BGCA) Ambassador after being inducted to their Hall of Fame in 2015. In addition, he leads up a literacy program for underprivileged youth in the BGCA, called Read with Reed 83 Challenge.

On January 9, 2011, Reed was announced to be one of the 15 finalists to be considered for the Hall of Fame Class of 2011. He, Cris Carter, and Tim Brown were once again passed over. The same trio were among the 15 finalists for the Hall of Fame Class of 2012, and all three were once again passed over.

On February 2, 2013, Reed failed to get voted into the Pro Football Hall of Fame. He made the cut from 15 finalists to 10 last-ballot candidates, though, while Tim Brown finished his candidacy in the group of 15. Cris Carter made the Hall of Fame.

On February 1, 2014, Reed was selected to the Pro Football Hall of Fame. He was inducted on August 2, 2014.

On October 18, 2014, Kutztown University, Reed’s alma mater, renamed University Field to Andre Reed Stadium in his honor in a ceremony.