I’m looking forward to when my obligations with my current team have been honored, so I can get with the entire Panther family and start moving towards all of our goals of winning races and championships together. It’s great to be back.”

Wheldon became one of the winningest and most consistent drivers in open-wheel racing during stints with Andretti Green Racing and Chip Ganassi Racing. In 2005, he won both the Indianapolis 500 and the IndyCar Series championship during a season in which he won a league-record six races. The following season he won two more races and tied former teammate Hornish for the overall points lead at the end of the year but the title went to Hornish because he had more victories.

On 22 June 2008, his 30th birthday, he took his 15th career victory in the IndyCar Series after winning the 2008 Iowa Corn Indy 250 over Hideki Mutoh and Marco Andretti. He donated his winnings to help the victims of the recent tornadoes and flooding which had occurred in Iowa.

Wheldon was released from his drive at Ganassi on 2 September 2008. He was replaced by Dario Franchitti; "I have enjoyed these last three seasons with Target Chip Ganassi Racing, but will be moving on to pursue a very exciting opportunity for 2009," Wheldon said. It would later turn out to be a return to former team Panther Racing. Wheldon drove the Panther car to a second place finish in the 2009 Indianapolis 500, the second Indy 500 runner-up finish in a row for the team. However, his strong start to the season faded and Wheldon failed to crack the Top 10 in 7 of the last 8 races of the year. The following year Wheldon again showed strong at the Indianapolis Motor Speedway, finishing second at the 2010 Indianapolis 500. This gave Panther its third straight runner-up finish at Indy. This time, Wheldon remained competitive all year, challenging for wins on the oval tracks.

Despite strong showings in the Panther Racing No. 4 car, Wheldon still failed to win a race during his time with the team. This led to his being replaced at Panther Racing by the young American driver (and 2009 Indy Lights champion) J.R. Hildebrand. Wheldon attempted and won the 2011 Indianapolis 500 with Bryan Herta Autosport in stunning and ironic fashion after inheriting the lead with metres to go after Hildebrand wrecked going into the final turn trying to get around the decelerating Charlie Kimball with too much velocity, being the first driver in Indy history to win the race by leading a single lap. Wheldon was very emotional after the win, due to not having a ride for the rest of the season and concerning his mother who had recently been diagnosed with Alzheimer's Disease, to whom he partially dedicated his victory. It was Wheldon's first series win in three seasons.

At the 2011 IZOD IndyCar World Championship at Las Vegas Motor Speedway on 16 October 2011, Wheldon was involved in a 15-car accident during lap 11 of the race. He was taken to a local hospital with what were described as "serious injuries" and he died shortly after he got there. He was 33.