O'Ward has continued racing at AMSP the next season, partnering Felix Rosenqvist. After struggling with strategy and qualifying at Barber and St. Petersburg O'Ward and McLaren's form improved significantly during the double header at the Texas Motor Speedway. O'Ward took third in the Genesys 300 and took his maiden IndyCar victory in the following XPEL 375. He became the first Mexican driver to win an IndyCar race since Adrian Fernandez did so in 2004 and the first Chevrolet driver not from Penske to win a race since 2016. A fourth place finish at the 2021 Indianapolis 500, his second career pole position at race one Detroit, and a third place finish in Race One vaulted O'Ward into second place in the championship behind fellow second year driver Alex Palou. In Race Two at Detroit, O’Ward earned his second career win and first on a street course, giving him his first championship lead in IndyCar by a single point. O'Ward lost the championship lead after Palou won the following weekend but had quality drives at Road America and Mid Ohio to keep himself within striking distance of the championship lead and ahead of Scott Dixon for second place before the summer break. A difficult weekend in Nashville briefly caused O'Ward to cede second place to Scott Dixon but O'Ward took second place back and cut out a large portion of Palou's points lead with a pole position bonus point and a top five finish at the second round on the IMS Road Course while Palou retired with an engine failure and Dixon finished mid pack. O'Ward seized momentum in the championship the following weekend at Gateway, finishing second to Josef Newgarden to take a ten point lead over Palou heading into the end of the season West Coast trip.