[13] Head coach Chip Kelly named Poyer the fourth cornerback on the depth chart, behind Cary Williams, Bradley Fletcher, and Brandon Boykin.

[14][15] He made his professional regular season debut in the Philadelphia Eagles' season-opener at the Washington Redskins and recorded three combined tackles in their 33–27 victory.

[23] During training camp, he competed for a roster spot as a backup safety against Jim Leonhard, Johnson Bademosi, Josh Aubrey, Robert Nelson, and Darwin Cook.

[24][25] Head coach Mike Pettine named Poyer the backup free safety, behind Tashaun Gipson, to start the regular season.

[30] On October 18, 2015, Poyer earned his first career start in place of Gipson, who suffered an ankle injury the previous week.

[33] On November 15, 2015, Poyer recorded four combined tackles, broke up a pass, and made his first career interception by Ben Roethlisberger during a 30–9 loss at the Pittsburgh Steelers in Week 10.

In Week 14, he recorded two solo tackles and made his first career sack on quarterback Blaine Gabbert during a 24–10 victory against the San Francisco 49ers.

[35] Following the game, head coach Mike Pettine was officially relieved of his duties by general manager Ray Farmer after the Cleveland Browns finished the season with a 3–13 record.

[40] On September 25, 2016, Poyer collected a career-high 13 combined tackles (ten solo) and deflected a pass during a 30–24 loss at the Miami Dolphins in Week 3.

[41] On October 16, 2016, Poyer collected three solo tackles before exiting the Browns' 28–26 loss at the Tennessee Titans due to an injury.

[42] During the second quarter, Poyer was in the midst of covering a punt when he was hit by an illegal blindside block by running back Antonio Andrews.

The Titans were penalized 15 yards for unnecessary roughness, and Poyer was immediately rushed to the hospital, where he was diagnosed with a lacerated kidney and a possible concussion.

[46] He immediately signed with the Bills on the first day of free agency and was reunited with the Cleveland Browns' former assistant defensive backs coach, Bobby Babich.

He intercepted a pass by Tom Brady that was intended for Kenny Britt and returned it for a 19-yard touchdown in the second quarter to mark the first score of his career.

[53] He finished his first season with the Buffalo Bills with a 94 combined tackles (63 solo), 13 pass deflections, five interceptions, two sacks, and a touchdown in 15 games and 15 starts.

[55] On January 7, 2018, Poyer started in his first career playoff game and recorded five combined tackles during a 10–3 loss at the Jacksonville Jaguars in the Wild Card Round.

[57] Though the Bills missed the playoffs in 2018, their defense, including Poyer and Hyde, remained stout, quietly finishing with the second-fewest passing yards allowed in the league.

[60] In week 11 against the Dolphins, Poyer forced a fumble on wide receiver Allen Hurns and recovered the football in the 37–20 win.

[61] In week 15 against the Steelers on Sunday Night Football, Poyer intercepted a pass thrown by rookie quarterback Devlin Hodges in the endzone and recovered a fumble forced by teammate Trent Murphy on Diontae Johnson during the 17–10 win.

[62] In week 16 against the Patriots, Poyer recorded 11 total tackles and forced fumble on running back Rex Burkhead which was recovered by teammate Micah Hyde in the 24–17 loss.

[66] He finished the 2020 season with two sacks, 124 total tackles (91 solo), two interceptions, five passes defended, and two forced fumbles in 16 games and starts.

[71] Throughout the 2022 season, Poyer battled multiple injuries and missed several games but remained a key part of Buffalo's defense.

[72] Notably, he rode in a van to the Bills' game against the Kansas City Chiefs as he was unable to fly due to a collapsed lung.

[80] Poyer started 16 games for the Dolphins in 2024, receiving praise for his leadership in the locker room, though he did not record an interception for the second year in a row.