IRL 2005

After the 2004 season, following much speculation as to where Patrick would race in 2005, Rahal Letterman Racing officially announced that Patrick would drive in the IRL IndyCar Series for 2005.

On May 29, 2005, Patrick became only the fourth woman to race in the Indianapolis 500, following Janet Guthrie, Lyn St. James, and Sarah Fisher. After posting the fastest practice speed of the month (229.880 mph / 369.956 km/h) during the morning practice session for the first day of qualifications (May 15), she made an error in the first turn of her first qualifying lap, and failed to capture the pole position, which instead went to Tony Kanaan; Patrick's fourth starting position, however, was still the highest ever attained for the race by a female driver.

Patrick became the first female driver to lead the race at Indianapolis, first when acquiring it for a lap near the 125 mile mark while cycling through pit stops, and late in the race when she stayed out one lap longer than her rivals during a set of green-flag pit stops. Patrick overcame two crucial blunders to finish fourth in the race, the same position in which she started. Her car stalled in the pits about halfway through the 500-mile race, dropping her to the middle of the field. Shortly after reclaiming a spot in the top 10, Patrick spun on a caution period just before an intended green flag, causing a four car accident. The accident caused damage to the nose and front wing of her car. Her pit crew promptly made repairs, and due to the subsequent yellow, was able to rejoin having lost only 1 place. When the leaders pitted for fuel on lap 172, Danica took the lead once more, lost it on lap 184, and then regained it on a restart with 11 laps to go. However, as she had not pitted for fuel, Danica needed one more long yellow in order to reach the finish without having to refuel. On lap 194, eventual race winner and 2005 series champion Dan Wheldon passed her as she was forced to slow in order to conserve fuel, and she was quickly passed by both Bryan Herta and her teammate Vitor Meira. Patrick's fourth place was the highest ever finish for a female driver, besting the previous record of ninth set by Janet Guthrie in 1978. Danica led 19 laps overall.

In 2005 she finished 12th in the IRL IndyCar Series Championship, with 325 points.

On July 2, 2005, Patrick won her first pole position, leading a 1,2,3 sweep by Rahal-Letterman Racing at Kansas Speedway. She became the second woman to accomplish this feat in the IRL IndyCar Series, the first being Sarah Fisher in 2002 at Kentucky Speedway. On August 13, she won her second pole at Kentucky Speedway, although this time, rain prematurely ended qualifying and position was determined by speeds achieved during practice.

In January 2006, Patrick competed in the Rolex 24 at Daytona along with co-driver Rusty Wallace. The 24 hour event was her longest race to date.