The 25-year-old Mexican latched on to an early morning tow and hurtled around with a flying lap of 228.861mph to claim the top spot on the leaderboard.
Scott McLaughlin’s #3 Team Penske Chevrolet, wo led Wednesday’s practice, continued to showcase strong pace after a tow lap of 227.316mph put him second overall.
Reigning and two-time IndyCar champion Alex Palou ended up third fastest of the day with another tow-supported run at 226.915mph for his #10 Chip Ganassi Racing Honda.
Colton Herta’s best lap of 226.828mph was good enough for fourth overall. He also claimed the best no-tow lap on the day – which came in the opening hour – as his #26 Andretti Global Honda nailed a best of 224.182mph.
Defending race winner Josef Newgarden was fifth on the overall speed charts after his #2 Team Penske Chevrolet managed a tow-assisted lap of 226.684mph.
The rest of the top 10, all tow-assisted runs, were led by Marco Andretti (Andretti Herta) in sixth, followed by rookie Linus Lundqvist (Chip Ganssi Racing), Ed Carpenter (Ed Carpenter Racing), 2018 Indy 500 winner Will Power (Team Penske) and 2008 Indy 500 champion Scott Dixon (Chip Ganassi Racing).
Directly behind Herta on the no-tow list was Andretti Global team-mate Kyle Kirkwood, who was able to run a lap of 223.387mph.
Four-time Indy 500 winner Helio Castroneves was third among single-car runs, with his No. 06 Meyer Shank Racing Honda unleashing a lap of 222.852mph.
Graham Rahal (Rahal Letterman Lanigan Racing) and Rinus VeeKay (Ed Carpenter Racing) were fourth and fifth, respectively, on the no-tow list.
There were multiple incidents on the day, with Lundqvist the first to experience a practice crash this year at the Indianapolis Motor Speedway.
Lundqvist ran into trouble just 90 minutes into the session after his #8 Chip Ganassi Racing Honda, which was tailing the Arrow McLaren duo of O’Ward and Rossi, touched the inside kerb of Turn 2, which thrust the rear-end of his car into the outside wall.
The momentum carried him down the backstretch, where he fortunately avoided the inside wall before coming to a stop. Lundqvist, one of seven rookies entered in the event, was able to walk away under his own power after being carefully assisted out of the car by IndyCar’s AMR Safety Team.
“I'm alright,” said Lunqvist, who ran 23 laps. “It's my mistake. I know exactly what I did; I touched the kerb in (Turn) 2 and I couldn't hold onto it. Something they talk about often around this place. But it's just a mistake in my part and obviously my team has to pay the price for it, so yeah, it sucks.”
The team was able to preserve going to a back-up car, instead opting to replace the rear assembly, bodywork and replace the floor.
The other incident involved 2022 Indy 500 winner Marcus Ericsson, who crashed with just over two hours remaining.
He was the last driver in a line of four cars when he grazed the kerb in Turn 4 before taking a 180-degree spin and slapping the left side of his car into the outside wall. From there, his #28 Andretti Global Honda drifted across the track and nosed into the inside wall before making heavy contact with the attenuator at pit entrance.
Ericsson got out gingerly but also walked away under his own power. He logged 79 laps before the incident, with a best of 224.592mph to stand 18th overall.
“I think I brushed the kerb a little bit and that's probably enough to send it,” he said. “And then you're a passenger, so yeah. Very disappointed.
“Very sorry for my team. They've done a very good job and they have a lot of work ahead of them now, so that's probably the worst of the whole thing."
Andretti Global COO Rob Edwards, who also calls strategy for Colton Herta, confirmed to Autosport the damage sustained to Ericsson's crash was severe enough that the team has elected to move to a back-up car.
NASCAR star Kyle Larson’s day began in the garage as his #17 Arrow McLaren-Rick Hendrick Chevrolet underwent an engine change. His car arrived on pit lane at 11:15am ET, 75 minutes after practice began.
Although Larson, the 2021 Cup Series champion, managed to get out with several hours remaining to get acclimated, he reported further issues with his car and only logged 29 laps with a best of 222.805mph in the tow to place 22nd overall.
He was back out on track again at the end of the day and recorded a decent no-tow lap of 222.554mph during a qualifying simulation.
Alexander Rossi had a couple of moments in the early portion of the day, beginning with misjudging the entry in Turn 2 and briefly catching the apron. Roughly an hour later, his #7 Arrow McLaren Chevrolet was squeezed next to the pit wall on the inside of the front straight while attempting a pass on the #77 Juncos Hollinger Racing Chevrolet of Romain Grosjean.
There was a brief spell of green flag running after Ericsson’s crash and the extended caution to repair the attenuator. However, the rain persisted as the caution came out once again with 90 minutes remaining in the session.
It dried sufficiently for running to resume with 25 minutes on the clock, only for Conor Daly to bring out a yellow when he coasted to the pits with a smoking right-front corner on his Dreyer & Reinbold entry.
More rain sprinkles ended the day with 10 minutes to go.
