McDowell took advantage of a slow pitstop by Daniel Suarez to extend his lead in Stage 2 and never looked back at Indianapolis.
The 38-year-old then saw off Chase Elliott down the home straight as the race ended with a 77-lap green flag run, to win by 0.937 seconds.
Although McDowell was in contention to make the 2023 playoffs based on points, his victory locks him into the 16-driver field.
McDowell’s only other Cup win came in the 2021 Daytona 500, which automatically put him into the playoffs that year.
The win by McDowell and his #34 Front Row Motorsports team also gives Ford three consecutive wins for the first time since the 2020 season.
“Oh man, this is a dream come true. I’m just so thankful for everybody at Front Row Motorsports and [owner] Bob Jenkins,” McDowell said. “Man, we had a fast Ford Mustang today. We had the fastest car.
“I’m just so thankful to still be driving in the Cup series. To put on a performance like that, I don’t know if it was dominant, but it felt pretty dominant to me.”
Asked about Elliott’s charge in the final laps, McDowell said: “I was just trying to pace myself. I figured there would be a late-race caution and I didn’t want to burn my stuff up. I was just trying to maintain that gap.”
Having narrowly missed out on victory, Elliott must win one of the two races left before the playoffs begin to be in the title battle.
Suarez, who started on the pole, also faces a similar prospect having finished third, as Tyler Reddick took fourth, who has already booked his playoff place, and Alex Bowman rounded out the top five – another on the cusp of the playoffs.
Chase Briscoe secured his best result since fourth place at Martinsville back in mid-April with sixth place, ahead of playoff trio Martin Truex Jr, Kyle Larson, and Christopher Bell.
Superstar guest driver Shane van Gisbergen impressed again as he completed the top 10 to follow up his win on debut back in Chicago.
The three-time Supercars driver led the strong international contingent, with fellow Supercars star Brodie Kostecki in 22nd, 2010 Le Mans 24 Hours winner Mike Rockenfeller 24th, 2009 Formula 1 world champion Jenson Button 28th and WEC star Kamui Kobayashi in 33rd.
NASCAR Cup - Indianapolis Road Course race results
