Three red flags late in the race set up a two-lap shootout with Ericsson leading the restart before Newgarden, who moved from fourth to second by virtue of race control, blasted past him to give owner Roger Penske his 19th Indy 500 win but first since his purchase of the team in 2019.
"I'm so thankful. (I) started as a fan in the crowd, it is amazing. I love this city," said Newgarden.
"I was emotional in the last 10 laps, I knew I was in a position to fight. I'm just thankful that the team, everyone, that we finally got this done.
"I was trying to put it off, it's not going to define your career winning the race here, but everyone seems to want to make it a defining moment so for me it's impossible not to look at it that way."
It was Newgarden's first 500 victory in his 12-year career.
