The 2016 season was the Buffalo Bills' 47th in the National Football League (NFL), their 57th overall, their fourth under general manager Doug Whaley and their second under head coach Rex Ryan.

The Bills hoped to improve on their 8–8 record from 2015, the team's first since 2002, but a 34–31 overtime loss to the Miami Dolphins in Week 16 eliminated the Bills from playoff contention for a 17th season in a row, extending the longest active drought among all four North American major professional sports leagues.

On January 10, 2016, one week after the 2015 season ended, Doug Whaley signed a three-year contract extension to remain the Bills general manager.

Three days later, Ryan hired former NFL standout Ed Reed to be an assistant defensive backs coach.

On September 16, 2016, less than 24 hours after losing 37–31 to the New York Jets in their home opener in a game in which the defense failed to stop Jets running back Matt Forte, instead of firing defensive coordinator Dennis Thurman, Ryan pretty much sealed his own fate by firing offensive coordinator Greg Roman and promoting running backs coach Anthony Lynn to the position.

Lynn would later be promoted to interim head coach on December 27, 2016, when the Ryan brothers were fired after the 34–31 overtime loss to the Dolphins eliminated the team from the playoffs.

With the win, the Bills improved to 6–5, but defensive tackle Corbin Bryant and wide receiver Walt Powell had to miss the rest of the season.

After the Bills took the lead with a touchdown inside the two-minute warning at the end of the fourth quarter, the Dolphins took the game to overtime with a 55-yard field goal with six seconds on the clock.

Anthony Lynn served as interim head coach, and EJ Manuel made his first start of the season, though he was benched in the 4th quarter as Cardale Jones took over.

This game included a notable flaw on Bills' special teams during a botched kickoff play.