To begin the 2008 season, her second with AGR, Patrick scored her best career Homestead finish of 6th. She followed that up with another top 10 by scoring a 10th place finish at St. Petersburg.

Patrick won at Twin Ring Motegi in the Indy Japan 300 on April 20, 2008, becoming the first woman to win an IndyCar race,  joining the ranks of drag racer Shirley Muldowney, who won three NHRA Top Fuel Championships, as a "first female" winner in the top tier of American motorsports. Patrick took the Indy Japan 300 after the race leaders were forced to pit for fuel in the final laps. She finished 5.8594 seconds ahead of the Brazilian pole-sitter Helio Castroneves on the 1.5-mile (2.4 km) Twin Ring Motegi oval.

Her team owner, Michael Andretti, commented, "I'm thrilled for her that the monkey is finally off of her back."
A mechanical problem late in the race RoadRunner Turbo 300 at Kansas Speedway forced Patrick to retire early from the race.

During practice for the 2008 Indianapolis 500, Patrick's car struck a member of Dale Coyne Racing's pit crew when she came into the pits on May 9th. During the Indianapolis 500 on May 25, 2008, she retired from the race early after a collision in the pitlane. As Ryan Briscoe exited his pitbox the two cars collided, damaging Patrick's left rear suspension and eliminating both from the race. After being pushed back to her own pit, Patrick left her car and headed down pit road towards Briscoe's pit at which point IMS security intervened, preventing an on-track confrontation.

Following Indy, Patrick finished 9th at Milwaukee and 10th at Texas, with both races ending under yellow flag conditions. At Iowa and Richmond she stayed out of the many crashes during these races and finished 6th in each event.

Patrick will test for Formula One team Honda in November 2008.