As the second pick of Round 2 of the 2021 NBA G League Draft, Brissett joined the Mad Ants for the Single Site season in Orlando. His 18.6 points per game at the single site earned him All NBA G League Second Team honors.
On April 1, 2021, Brissett earned his NBA Call-Up by way of a 10-day contract with the Indiana Pacers. He would sign a second 10-day contract, and then on April 21 upon that one expiring, Brissett would sign a standard three-year deal with the Pacers through the end of the 2022-2023 season.
On April 20, 2021, Brissett made his first career NBA start in a 109–94 loss to the San Antonio Spurs, scoring 13 points on 5-of-8 shooting from the field and 3-of-5 from three, along with six rebounds and a steal. The following day is when Brissett would sign his multi-year contract and then started that night's game against the Oklahoma City Thunder scoring 23 points, grabbing 12 rebounds, and recording 3 blocks. May 18, 2021, Brissett scored 23 points with five rebounds and two assists in a 144–117 NBA Playoffs play in win over Charlotte.
Brissett started 16 of the 21 games he played in during his call-up season in 2021, averaging 10.9 points and 5.5 rebounds.