The biggest highlight of Reich's college career was the comeback he led against the Miami Hurricanes on November 10, 1984 at the Orange Bowl Stadium. Reich came off the bench to play for Stan Gelbaugh, who had previously replaced him as the starter after Reich separated his shoulder in the fourth week of the season against Wake Forest. Quarterback Bernie Kosar had led Miami to a 31–0 halftime lead. At the start of the third quarter, Reich led the Terrapins on multiple scoring drives. Three touchdowns in the third quarter and a fourth at the start of the final quarter turned what was a blowout into a close game. With Miami leading 34–28, Reich hit Greg Hill with a 68-yard touchdown pass, which deflected off the hands of Miami safety Darrell Fullington, to take the lead. Maryland scored once more to cap a 42–9 second half, and won 42–40, completing what was then the biggest comeback in NCAA history.
Reich was drafted by the Buffalo Bills in the third round (57th overall) in the 1985 NFL Draft. The Bills already had drafted future Hall of FamerJim Kelly in 1983 and when Kelly signed with the Bills in 1986, Reich was relegated to the backup role.
Reich got his first start when Kelly went down with a shoulder injury in 1989. Reich led the Bills to two straight victories. He rallied the Bills in the fourth quarter by throwing two drives down the field for a 23-20 victory over the previously unbeaten Los Angeles Rams. This first game for Reich occurred in front of a Rich Stadium crowd of 76,231 and a Monday Night Football audience.
Reich returned the following year, however, when Kelly was injured again late in the 1990 season. Reich provided the Bills with two key wins, clinching them the AFC East title and home field advantage throughout the playoffs.
During the final game of the 1992 regular season, the Houston Oilers defeated Buffalo 27–3 in Houston, where Kelly suffered strained ligaments in his knee and yielded to Reich to finish the game in his place. With Kelly out, Reich took the reins as the starter for the wild card game the following week, on January 3, 1993. The wild card game was a rematch with the Oilers, hosted in Buffalo, where they led the Bills 35-3 early in the 3rd quarter, but Reich then led the Bills on a 38-3 run en route to a 41-38 overtime victory, the largest comeback in NFL history. Reich started his second consecutive playoff game, as the Bills defeated the Pittsburgh Steelers 24-3 in the divisional round. This made Reich one of a handful of quarterbacks who is undefeated as a starter in post-season play, as well as the only one with more than one start to his credit. Kelly recovered and started the AFC Championship where the Bills defeated the Miami Dolphins 29–10. During Super Bowl XXVII, the Bills faced the Dallas Cowboys and Reich again replaced an injured Kelly in the first half of the Super Bowl. Reich led the Bills to 10 points, though a touchdown came on an illegal pass across the line of scrimmage that wasn't called, make the score 31-17, with a possible comeback well within the Bills' capability as the 3rd quarter concluded. However in the 4th quarter, the Cowboys scored 21 unanswered points to win 52-17, and Reich finished the game with two interceptions.
After giving the Bills one more comeback victory late in the 1993 NFL season, Reich was picked from the Bills in the 1995 expansion draft to join the Carolina Panthers to start off their first year. He threw the first touchdown pass in franchise history to former Bills player Pete Metzelaars in Memorial Stadium in Clemson, as Bank of America Stadium was still under construction. The Panthers had drafted Kerry Collins as their intended franchise quarterback, but Reich was the starter for the first three games until Collins was deemed ready to take the starting job.
Reich was then signed by the New York Jets where he started for seven games in 1996.
In 1997 Reich signed with the Detroit Lions, reuniting him with his coach at Maryland, Bobby Ross. Reich appeared in 6 games in 1997, all in relief, and 6 games in 1998, including 2 starts. Reich retired following the 1998 NFL season.
In 2014, NFL Hall of Fame Executive Bill Polian, who was general manager of the Bills when they drafted Frank Reich, called him "the greatest backup quarterback in NFL history."
In 2008, he served as an offensive assistant and quarterbacks coach for the Indianapolis Colts. After Tony Dungy retired early in 2009, Jim Caldwell (former Colts quarterback coach) replaced Dungy and Reich took his place as the new quarterbacks coach. Reich switched to Wide Receivers Coach in 2011 but was dismissed when the entire coaching staff was released. He was the wide receivers coach for the Arizona Cardinals in 2012 under head coach Ken Whisenhunt, but both Reich and Whisenhunt (along with other offensive coaches) were dismissed on December 31, 2012. He was hired by the San Diego Chargers along with Whisenhunt in 2013. When Whisenhunt left to become head coach of the Tennessee Titans, Reich was promoted to offensive coordinator. On January 4, 2016, he was fired from his position as offensive coordinator with the San Diego Chargers. On January 20th, 2016, he was hired as offensive coordinator with the Philadelphia Eagles.
Throughout Reich's NFL career, he remained a devout Christian. He is a motivational speaker utilizing the great comebacks and the importance of God as a main keynote of his speeches. He credits the song "In Christ Alone" by Michael English as his inspiration. He belongs to the Premier Speakers Bureau where his main topics are communication and teamwork. Reich attended the Charlotte Campus of Reformed Theological Seminary, Charlotte, North Carolina, where he earned a Master of Divinity degree. He served as president of RTS' Charlotte campus from 2003-2006. Reich was also a pastor at Ballantyne Presbyterian until he moved to Indianapolis.
While living in Buffalo, New York in the early 90s, Reich met a man named Jim Case whom he hired to build his deck and refinish his basement. A friendship between Reich and Case formed and they started a company together called Pro Display Inc. which specialized in sports memorabilia. Their main item was a football stand inspired by Reich's father, who created a wooden stand shaped like a football field where the goal posts held up the football. Reich had co-founded a retail business in the 90s that he started with friend Boomer Esiason and two others. They were part owners of Jim and Chuck's Boot Shop. The store expanded over the New England area with fifteen stores where they still remain today.