On March 13, 2013, Ryan participated at Rutgers' pro day along with Marcus Cooper, Duron Harmon, Steve Beauharnais, Mark Harrison, Brandon Jones, Jawan Jamison, Khaseem Greene, and seven others.

[14] Ryan competed for a starting cornerback job behind Alfonzo Dennard, Aqib Talib, Kyle Arrington, and Ras-I Dowling.

Head coach Bill Belichick named Ryan the fourth cornerback on the Patriots' depth chart to begin the 2013 season, behind Dennard, Talib, and Arrington.

[19] During a Week 12 34–31 victory over the Denver Broncos, Ryan was named the starter over Alfonzo Dennard, who had been battling a knee injury.

[21][22] Three weeks later against the Baltimore Ravens, Ryan had a tackle, a season-high two pass deflections, and intercepted Joe Flacco twice during the 41–7 road victory.

[23] Ryan finished his rookie year with 35 combined tackles (29 solo), 1.5 sacks, five interceptions, 10 pass deflections, and a forced fumble in 16 games and seven starts.

Ryan competed against Alfonzo Dennard, Darrelle Revis, Kyle Arrington, and Brandon Browner for the vacant starting cornerback position left by the departure of Aqib Talib.

[30] Ryan finished his second professional season with 42 combined tackles (29 solo), six pass deflections, and two interceptions in 16 games and six starts.

[33] On February 1, 2015, Ryan appeared in Super Bowl XLIX and made a tackle and pass deflection in a 28–24 victory over the Seattle Seahawks.

[34] Ryan competed with Malcolm Butler, Justin Green, Bradley Fletcher, and Tarell Brown for the vacant starting cornerback positions throughout training camp after Darrelle Revis, Alfonzo Dennard, Kyle Arrington, and Brandon Browner left during the off season.

[35] Head coach Bill Belichick named him the third cornerback on the depth chart behind Malcolm Butler and Tarell Brown to start the 2015 season.

[41] He was named the indefinite starting cornerback for the remainder of the season after the game, replacing Tarell Brown who was placed on injured reserve.

[citation needed] Ryan finished the 2015 season with 74 combined tackles (58 solo), a then career-high 14 pass deflections, and four interceptions in 16 games and 14 starts.

[44] On January 16, 2016, he made his first NFL postseason start and recorded nine combined tackles during a 27–20 victory over the Kansas City Chiefs in the Divisional Round.

[45] The following week, he made five solo tackles and defended a pass, as the Patriots lost on the road 18–20 to the Broncos in the AFC Championship.

[48] Ryan was delegated to the third cornerback on the depth chart for Weeks 7–8 after Eric Rowe emerged as the starter after being inactive for the first five games while rehabbing an ankle injury.

[51] On December 18, 2016, Ryan recorded seven solo tackles, deflected a pass, and intercepted quarterback Trevor Siemian as the Patriots defeated the Broncos on the road by a score of 16–3.

[53] Ryan finished the 2016 season with a then-career-high 92 combined tackles (74 solo), 11 pass deflections, two interceptions, a sack, and a forced fumble in 16 games and 13 starts.

[65] Ryan entered the 2018 season as a starting cornerback alongside Adoree' Jackson and former Patriots teammate Malcolm Butler.

The score secured a 20–13 upset in Foxborough, allowing the Titans to play in the Divisional Round of the playoffs for the second time in three years.

[84] In Week 9 against the Washington Football Team, a day after his wife suffered an ectopic pregnancy, Ryan recorded his first interception of the season off quarterback Alex Smith with less than two minutes in the fourth quarter to secure a 23–20 Giants' win.

[95] Ryan finished the 2022 season with 37 total tackles (24 solo), three pass deflections, an interception, and a forced fumble in nine games and six starts.

[96] On December 6, 2023, Ryan signed with the San Francisco 49ers after starting safety Talanoa Hufanga suffered a season-ending torn ACL.

Every month on the 26th—the day corresponding to his jersey number—Ryan posts a photo on social media with a dog that is in need of adoption along with the hashtag #ryansmonthlyrescue.