Slayton was drafted by the New York Giants in the fifth round, 171st overall, of the 2019 NFL draft.[7] He was the 18th wide receiver taken that year.[8]
In Slayton's first NFL game, a Week 3 32–31 victory over the Tampa Bay Buccaneers, he had three receptions for 82 yards from fellow 2019 NFL draft pick Daniel Jones.[9] In his third game, a 28–10 loss to the Minnesota Vikings, he scored a 35-yard touchdown.[10] In Week 8 against the Detroit Lions, Slayton caught two passes for 50 yards, both of which ended up being touchdowns, in the 31–26 loss.[11] During Week 10 against the New York Jets, Slayton finished with 10 catches for 121 receiving yards and two touchdowns as the Giants lost 27–34.[12] During Monday Night Football against the Philadelphia Eagles in Week 14, Slayton finished with five catches, all in the first half, for 154 receiving yards and two touchdowns as the Giants lost 17–23 in overtime.[13] Overall, Slayton finished his rookie season with 48 receptions for 740 receiving yards and eight receiving touchdowns, leading the Giants in receiving yards for the 2019 season.[14][15]
2020
In the Giants' 2020 regular season opener against the Pittsburgh Steelers on Monday Night Football, Slayton had six receptions for 102 receiving yards and two receiving touchdowns during the 26–16 loss.[16]
In Week 5 against the Dallas Cowboys, Slayton recorded eight catches for 129 yards during the 37–34 loss.[17] He finished the 2020 season with 50 receptions for 751 receiving yards and three receiving touchdowns.[18]
2021
In the Giants' Week 2 game against the Washington Football Team, Slayton finished with three receptions for 54 yards and a touchdown, but dropped a pass in the end zone in the fourth quarter.[19] He finished the 2021 season with 26 receptions for 339 receiving yards and two receiving touchdowns in 13 games and five starts.[20]
2022
In Week 10 game against the Houston Texans, Slayton averaged 31.7 yards per catch, a career-high for a single game. He also had a 54 yard touchdown and finished with three receptions for 95 yards and a touchdown in the 24–16 win.[21] He finished the season with 46 catches for 724 yards and two touchdowns through 16 games and 11 starts.[22]
2023
On March 16, 2023, Slayton signed a two-year contract extension with the Giants.[23] Slayton finished the 2023 season with 50 receptions for 770 yards and four touchdowns.[24]