Reich played college football for the Maryland Terrapins and was selected by the Buffalo Bills in the third round of the 1985 NFL draft.

Reich, who is of German descent, attended Cedar Crest High School in Lebanon, Pennsylvania, where he played baseball, football, and basketball.

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.

In Super Bowl XXV, kicker Scott Norwood famously missed the potential game winning field goal wide-right, partially because Reich, as the holder on the attempt, mistakenly aligned the laces to the right, positioning the kicked ball to fade right once in the air.

Reich provided the Bills with two key wins, clinching them the AFC East title and home field advantage throughout the playoffs.

Reich started his second consecutive playoff game, as the Bills defeated the Pittsburgh Steelers 24–3 in the divisional round.

[9] After giving the Bills one more comeback victory late in the 1993 NFL season, Reich signed with the expansion Carolina Panthers in March 1995 to start off their first year.

[10] He threw the first touchdown pass in franchise history to former Bills player Pete Metzelaars in Atlanta against the Falcons.

[23] On January 20, 2016, Reich was hired as the offensive coordinator for the Philadelphia Eagles[24] He went on to win Super Bowl LII over the New England Patriots with the team in the 2017 season.

[26][27][28] After losing his first career game against the Cincinnati Bengals, Reich earned his first win as a head coach over the Washington Redskins.

[29] In Week 3 against his former team the Eagles, with the Colts down 20–16 with seconds left in the game, Reich pulled starting quarterback Andrew Luck and put in Jacoby Brissett to attempt a Hail Mary pass from his own 46-yard line.

[30] The following week against the Houston Texans, Luck led the Colts back from down 28–10 in the third quarter, including a game-tying two point conversion with :51 left, however the team lost in overtime, 37–34.

Reich was the center of controversy after Indianapolis failed to convert a 4th and 4 on their own 43 and the Texans kicked the game-winning field goal, although he afterward said "I'll just address it now.

[33][34][35] Following Luck's unexpected retirement ahead of the 2019 season, Reich's Indianapolis tenure became noted for quarterback instability, with the team starting Brissett in 2019, Philip Rivers in 2020, Carson Wentz in 2021, and Matt Ryan and Sam Ehlinger in 2022.

[36][37] Reich guided the Colts to a playoff berth in 2020, however Rivers decided to retire after the season, forcing the team to look for another starting quarterback.

Wentz did rebound with the Colts, leading the team to a 9-6 record and having a 98% chance to make the playoffs with two games remaining in the season, according to FiveThirtyEight.

[39] Colts owner Jim Irsay had lost faith in Wentz for a lack of locker room leadership and ordered his release, despite having no starting quarterback lined up yet.

Following a Week 7 loss to the Tennessee Titans, Reich announced that Ryan had a shoulder injury and would be benched in favor of Ehlinger.

[45] At the time of his firing, the Panthers offense was 29th in sacks allowed while rookie quarterback Bryce Young struggled with one of the worst passer ratings in the league.

Frank Reich Sr. was a teacher in technology education and also a football coach at Lebanon High School, retiring in 1992.