Chastain returned to Spire Motorsports part-time. On September 21, 2020, Chip Ganassi Racing announced that Chastain would replace Matt Kenseth in the No. 42 Chevrolet in 2021. He finished a career-high 7th in the Xfinity standings with 27 top tens (the most of any driver that season) and 15 top fives (including five runner-up finishes), despite not winning a race. 2021 Chastain's Cup tenure with Ganassi began with a seventh-place finish in the 2021 Daytona 500, his best Cup finish up to that point. During the race's rain delay, he became the subject of a viral video from CGR in which he ordered food at a McDonald's (a team sponsor) drive-through for the team. In March, Chastain rejoined Niece for the Truck race at Atlanta. In May, he reunited with SS-Green Light Racing to drive their No. 07 car in the Xfinity Series race at Circuit of the Americas, replacing its normal driver, Joe Graf Jr. On June 30, 2021, Justin Marks, co-founder of Trackhouse Racing Team announced that he had purchased Chip Ganassi Racing's entire NASCAR operations after the 2021 season, leaving Chastain as a free agent. On August 3, 2021, it was revealed that Chastain would drive the No. 1 Chevrolet Camaro ZL1 for Trackhouse Racing's upcoming second Cup team, alongside the No. 99 of Daniel Suárez, in a multi-year deal beginning in 2022. 2022 Chastain began the 2022 season with a 40th place finish at the 2022 Daytona 500 and a 29th place finish at Auto Club Speedway. He then rebounded with a third place finish, while leading an at the time, career-high 83 laps at Las Vegas Motor Speedway and two runner-up finishes at Phoenix Raceway, and at Atlanta Motor Speedway, after recovering a two lap deficit upon crashing in lead position. Chastain scored his first career cup win at the Circuit of the Americas battling against Alex Bowman and A. J. Allmendinger. A month later, he claimed his second victory at Talladega. At the 2022 NASCAR All-Star Race, Chastain finished 22nd after going airborne from colliding with Kyle Busch, taking Chase Elliott out in the process. At the Indianapolis road course, Chastain crossed the line second to Tyler Reddick, but was penalized and scored 27th place for crossing the access road during the final restart. He finished third at the Phoenix finale and a career-best second place in the points standings. Feud with Denny Hamlin