Palou was signed by Chip Ganassi Racing to drive the No. 10 Honda for the 2021 IndyCar Series season. On 18 April 2021, Palou earned his maiden IndyCar Series victory in the season-opening race at Barber Motorsports Park. Palou added another podium for the season at the GMR Grand Prix. Palou finished second in the 2021 Indianapolis 500 to Hélio Castroneves' record-tying fourth victory. Palou's finish in the 500 vaulted him into the points lead for the championship. Palou then went on a run of podium finishes after the 500, although he briefly lost the points lead to Pato O'Ward in Detroit I. Palou finished third in the second race in Detroit, won at Road America after Josef Newgarden suffered a gearbox failure, and finished third at Mid Ohio to solidify his points lead in the championship over both Scott Dixon and O'Ward. Palou had an engine failure at the second round on the Indianapolis Road Course. He then gave up the points lead to O'Ward after he and Dixon were collected in an accident caused by Rinus VeeKay at Gateway.