On December 13, 2015, Gillislee scored his first career touchdown in a game against the Philadelphia Eagles. The following week, he scored his second career touchdown against the Washington Redskins. Gillislee became the first Bills running back since 1997 to produce touchdown runs of at least 50 yards in back-to-back weeks, a 60-yarder in Week 15 and a 50-yarder in Week 16. Overall, he finished his first season with the Bills with 267 rushing yards and three rushing touchdowns. On January 4, 2016, the Bills signed Gillislee to a contract extension. After Karlos Williams was released by the Bills after showing up out of shape, he stepped in and took the role of Bills' backup running back. Gillislee rushed for 577 yards on 101 carries. He posted 9 receptions and 50 yards receiving. Gillislee's 5.7 yards per carry led all NFL running backs during the 2016 season. When Gillislee was set to be a restricted free agent, the Bills placed an original round (fifth round) tender on Gillislee. On April 18, 2017, the New England Patriots extended a two-year, $6.4 million offer sheet to Gillislee, giving the Bills five days to match. On April 24, 2017, was signed by the New England Patriots. He was offered contracts by both the Bills and the Patriots, but the Bills declined to match the offer made by the Patriots. Gillislee signed for the Patriots on a two-year, $6.4 million deal. In order to sign him, the Patriots had to give up a 2017 5th round draft pick that was used to select Matt Milano. In the season opener against the Kansas City Chiefs on September 7, Gillislee had 15 rushes for 45 yards and a career-high three rushing touchdowns in his Patriots debut. However, he was stopped by the Chiefs defense on two fourth down plays in the 42–27 loss. In the game, Gillislee scored the first points of the 2017 NFL season with his first rushing touchdown in the first quarter. On September 17, in Week 2 against the New Orleans Saints, he followed up his Week 1 performance with 18 carries for 69 yards and a touchdown to bring his season total to four. After a promising start to the season, Gillislee’s role was limited and was inactive for seven games. He finished his first season in New England with 104 carries for 383 yards and 5 touchdowns and also caught a pass for 15 yards.