Ajayi followed up a Week 6 204-yard and two touchdown performance against the Pittsburgh Steelers with a 214-yard and one touchdown effort against AFC East rival Buffalo in Week 7, becoming only the fourth player in NFL history along with O. J. Simpson (twice), Earl Campbell, and former Miami Dolphin Ricky Williams to rush for over two hundred yards in two consecutive games. Ajayi was named AFC Offensive Player of the Week two weeks in a row for his 200+ rushing yards in back-to-back games in Weeks 6 and 7. In Week 16, on Christmas Eve, Ajayi recorded a third 200-yard game, again at the expense of the Buffalo Bills, including a 57-yard rush to set Andrew Franks up to kick a game-winning field goal in overtime. With his 32 carries for 206 yards and a touchdown, he became only the fourth player in NFL history to rush over 200 yards in three games in a single season, and the only player to do it as early as his second season. As a result of his Week 16 performance, he became one of only 15 players in NFL history with three or more career 200+ yard rushing games. In the 30-12 loss to the Pittsburgh Steelers in the Wild Card Round of the playoffs, he had 16 carries for 33 yards in his playoff debut. As a result of his successful season in 2016, he was named to the AFC roster for the 2017 Pro Bowl. In the Pro Bowl, he had seven rushes for 18 yards. He was ranked 69th on the NFL Top 100 Players of 2017 list by his fellow players.
Ajayi took part in the NFL's "My Cause, My Cleats" campaign in the 2016 season. The campaign allowed players to wear custom cleats supporting their favorite charities. His cause was multiple endocrine neoplasia. He is a lifelong fan of Arsenal F.C. in the English Premier League.