In his first match since a record 21st grand slam title in Australia, Nadal was a comfortable 6-3 6-2 winner over Denis Kudla, dropping only four points on serve.
Nadal is now 11-0 for the season, equalling the start he made in 2014, when his winning run was ended by Stan Wawrinka in the Australian Open final.
"I think I started playing well, a good victory in straight sets. That's always very positive for the confidence," said Nadal. "I think I played a very solid match for the first day.
"Of course, there are a couple of things that I can do better, but in general terms, I played well, so I can't complain at all."
Daniil Medvedev, who had also not played since the final in Melbourne, came through a tougher contest against Benoit Paire 6-3 6-4 in his opening match in Acapulco.
Medvedev held a two-set lead and looked in control before Nadal came roaring back to claim the Australian Open title, but the Russian could claim a landmark achievement in his first tournament since that heartbreak.
Medvedev, who faces Pablo Andujar next, will become world number one if he wins in Mexico, regardless of Novak Djokovic's performances in Dubai.
"It's always not easy to come back after some rest and some time off competition," he said. "I felt like my sensations were not at the top today, but I managed to fight until the end against a very tough opponent, and I'm happy that I managed to win."
Stefanos Tsitsipas racked up the 200th win of his career, holding off Laslo Djere to win two tie-breaks. He will now face J.J. Wolf, who surprised Lorenzo Sonego by fighting back from a set down to win 3-6 7-6 (9-7) 6-2.
Cameron Norrie was a straight-sets winner over Daniel Altmaier, while Yoshihito Nishioka battled through against veteran Feliciano Lopez.
Tommy Paul progressed after Matteo Berrettini retired when the American was poised to tie the match at one set all. John Millman also had to call an early halt to his match with Marcos Giron after a freak accident on court in which the Australian accidentally hit a ball into his eye.
At the Chile Open, home favourite Alejandro Tabilo beat Renzo Olivo in straight sets, while fifth seed Federico Coria was earlier knocked out by Yannick Hanfmann.
Miomir Kecmanovic defeated Marco Cecchinato, while there were also wins for seeds Sebastian Baez and Facundo Bagnis.