This would be the biggest of all for Ortiz, who won twice on the Mexican Golf Tour at the end of last year and is the younger brother of Carlos Ortiz, a PGA Tour winner who now plays in LIV Golf.
He finished at 11-under 131 at breezy Vallarta Vidanta, tied with US golfer Jake Knapp (64), Matt Wallace (65) of England and Sami Valimaki (67) of Finland.
Ortiz, who grew up in Guadalajara, played in the Masters as the 2019 Latin America Amateur champion, and qualified for the US Open in 2021 at Torrey Pines.
He is back on the Korn Ferry Tour this year after splitting time last year on the Asian Tour, Mexican Golf Tour and Tour Americas.
"The more I play, the more comfortable I feel and I start to realise that I have the game," Ortiz said.
"I've been doing good work and (trying to) put four rounds together. Hopefully, I can do that this weekend."
Ortiz started on the back nine and went out in 31, making birdie on all three of the par 5s, adding a pair of birdies in the 10-foot range.
He capped an otherwise even-par front nine with an eagle on the par-5 sixth.
"It was very clean, very stress free. I was glad to be able to make that eagle on six," Ortiz said.
"I was losing a little bit of momentum, but it was good to get that one back. Happy to be in the position I'm in."
First-round leader Erik van Rooyen picked up a pair of late birdies and salvaged a 69, leaving the South African one shot behind in outright fifth.
The Mexico Open is the first of two PGA Tour events in which the leading five players get into the next $US20 million ($A30 million) signature event at Bay Hill.
Wallace finished with a 30 on the front nine for a 65 that felt even better given his unusual approach to the sport.
Known to start slowly and then be forced to rally, Wallace and his caddie pretend they are already over par before teeing off. The decision for Friday was to 'start' at three over.
"Then I bogeyed it, so I was four over, so I had to get it back," he said.
"That sort of determination and focus really helped."
The only Australian to make the cut, Aaron Baddeley followed his opening-round 68 with a one-under 70 to sit tied for 31st.
Starting on the 10th, Baddeley carded three bogeys on the back nine as he ended the day seven shots off the leaders.
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