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 9. 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. Overall, she finished the 2008 IndyCar Series season in sixth place - the highest championship finish among American drivers for the 2008 season. Patrick was scheduled to test for Formula One team Honda in November 2008, however this was ultimately called off. As AGR stepped up to take over the A1 Grand Prix Team USA, Patrick is scheduled to be racing in the A1 series along with teammate Marco Andretti.

Prior to her win in Motegi, the most notable criticism of Patrick was that she had not won a race in three years of IRL competition and still garnered significant media attention. She is frequently promoted in mainstream and motorsport media, and has been compared to female athletes like Anna Kournikova for her apparent willingness to be marketed on her looks, examples being her appearance in FHM in April 2003 and Sports Illustrated in June 2005 and February 2008. Before 2008, some racing journalists, IndyCar fans, and other drivers claimed that Patrick's relatively low body weight gave her an advantage in the IndyCar series, which had a strict minimum weight set for the cars but which did not account for the driver's own weight. Patrick's height is 5 ft 2 in (1.57 m) and she weighs 100 pounds (45 kg; 7 st 2 lb). By comparison, the IRL's tallest driver in 2008 is 6 ft 3 in (1.91 m) Justin Wilson who weighs 176 pounds (80 kg; 12 st 8 lb). The Dallara cars used in the IRL series weigh between 1,530 pounds (690 kg) and 1,600 pounds (730 kg), excluding the driver and 22 U.S. gallons (83 L; 18 imp gal) of fuel. IRL President Brian Barnhart thinks the advantage is exaggerated, telling Dave Caldwell for The New York Times that Patrick's weight "had a minimal effect on the competition." With the IRL-Champ Car unification prior to the 2008 racing season, the rules were revised to define the minimum weight of the car as including the driver.

The narrow focus on weight differential, however, ignores the obvious and significant mechanical disadvantage Patrick continues to wrestle with in spite of many bigger and stronger drivers requesting the addition of power steering to Indy Cars. Several male drivers have made negative comments about Patrick's ability, as a woman, to race successfully. In May 2006, after an appearance on ESPN SportsCenter's Budweiser Hot Seat, Patrick made comments that ruffled the feathers of former NASCAR drivers. Former driver Richard Petty responded, in a separate interview, by stating, "I just don't think it's a sport for women, and so far, it's proved out. It's really not. It's good for them to come in. It gives us a lot of publicity, it gives them publicity. But as far as being a real true racer, making a living out of it, it's kind of tough." After Patrick's IRL win, she was praised by many drivers. NASCAR driver and former IRL champion Tony Stewart, for example, said "I think obviously she's got talent; she's been successful in every form of racing she's been in so far and I don't see why she wouldn't be successful here [in NASCAR]." Bob Margolis of Yahoo! Sports criticized Patrick for her actions after being taken out of the 2008 Indianapolis 500 after a pit road collision with Ryan Briscoe, writing that "Patrick’s drama queen theatrics have worn thin."

• Stand Up to Cancer (2008) (TV) .... Herself
• "Real Sports with Bryant Gumbel" (1 episode, 2008)
       - Episode dated 12 May 2008 (2008) TV episode
• "The Early Show" .... Herself (1 episode, 2008)
       - Episode dated 24 April 2008 (2008) TV episode .... Herself
• "Rachael Ray" .... Herself (1 episode, 2008)
       - Danica Patrick Teaches Rach to Drive! (2008) TV episode .... Herself
• "Late Show with David Letterman" .... Herself / ... (5 episodes, 2005-2008)
  ... aka Late Show Backstage (USA: title for episodes with guest hosts)
  ... aka Letterman (Australia)
  ... aka The Late Show (USA: informal short title)
       - Episode #15.101 (2008) TV episode .... Herself - Guest
       - Episode dated 20 March 2007 (2007) TV episode .... Herself
       - Episode dated 3 May 2006 (2006) TV episode .... Herself
       - Episode dated 20 September 2005 (2005) TV episode .... Herself
       - Episode dated 23 May 2005 (2005) TV episode .... Herself
• "Mike and Mike in the Morning" .... Herself (1 episode, 2008)
       - Episode dated 21 April 2008 (2008) TV episode .... Herself
• "The Big Give" .... Herself (2 episodes, 2008)
  ... aka Oprah's The Big Give (USA: complete title)
       - Episode #1.5 (2008) TV episode .... Herself
       - Big Give Road Test Challenge (2008) TV episode
• 2008 INDYCar Series Season Preview (2008) (TV) .... Himself
• The Red Dress Collection 2007 Fashion Show (2008) (V) .... Herself
• Who Made You? (2008) (TV) .... Herself
• "ESPNEWS" (1 episode, 2008)
       - Episode dated 27 February 2008 (2008) TV episode
• "Ellen: The Ellen DeGeneres Show" (1 episode, 2008)
       - Episode dated 22 February 2008 (2008) TV episode
• "American Chopper: The Series" .... Herself (1 episode, 2007)
  ... aka American Chopper (Australia)
       - Go Daddy Bike: Part 2 (2007) TV episode .... Herself
• "Rome Is Burning" .... Herself (4 episodes, 2006-2007)