Before the start of the 2016–17 season, Giles was selected to both Naismith and John R. Wooden Award preseason watchlists, while also finishing third in voting for ACC Preseason Rookie of the Year. At the conclusion of his freshman season, Giles announced that he would forgo his final three years of collegiate eligibility at Duke and enter the 2017 NBA draft.
Sacramento Kings (2017-20)
On June 22, 2017, Giles was selected by the Portland Trail Blazers with the 20th overall pick in the 2017 NBA draft. His rights were later traded to the Sacramento Kings on Draft night. On July 8, 2017, Giles signed his rookie scale contract with the Kings. On October 6, it would be announced that Giles would be out due to an injury and would return in early January of the next year. On January 18, 2018, it was announced that Giles would "not be introduced to NBA gameplay during the 2017–18 season but focus on more vigorous practice activity and individual workouts tailored to continue developing overall strength and aid ACL injury prevention."
Giles joined the Kings for the 2018 NBA Summer League, where he performed well. Before the start of the 2018–19 season, there were high expectations set for Giles and the Kings, which also mentioned Giles as a possible candidate for rookie of the year. In his NBA debut on October 17, 2018, Giles scored 2 points in a 123–117 season-opening loss against the Utah Jazz. On November 10, 2018, Giles was assigned to the Stockton Kings, the G-League affiliate of the Kings, where he scored 30 points in his debut for team. He was later recalled by the Kings. On April 3, the Kings would shut down Giles for the remainder of the season.
On October 31, 2019, the Kings declined Giles's option for the 2020–21 season worth $4 million. After the Kings signed centers Dewayne Dedmon and Richaun Holmes as free agents in the off-season Giles found himself out of the King's Big-man rotation. With injuries to Holmes and former No. 2 pick Marvin Bagley and the team trading Dedmon to the Atlanta Hawks, Giles found himself as the team's starting center on February 7, 2020, against the Miami Heat.
Portland Trail blazers (2020-present)
On November 22, 2020, Giles signed with the Portland Trail Blazers.