The sixth-seeded Lopez, who last played this event when he lost in the 2002 quarterfinals, ousted Querrey 4-6, 6-2, 6-3. Lopez, ranked No. 27 in the world, next faces Frenchman Adrian Mannarino, who advanced with a straight-set win over American Jack Sock.
"This is the first match I've played outdoors this season, and it's so different after playing the past month indoors," said Lopez, who lost in the second round at Memphis last week. "I started to be more aggressive in the second set."
Mannarino's 6-4, 6-2 win on the stadium court at the Delray Beach Tennis Center was his first in three matches against Sock this season.
"There's not a lot to say about this match," Mannarino said of his win against Sock, who was a wild-card entry after reaching the quarterfinals in Memphis last week. "It was not a good match, but I'm happy to win."
Monday's other singles results filled out the four qualifying spots in the 32-player field that includes No. 1 seed Tommy Haas of Germany.
Three Americans, including Wayne Odesnik, the No. 1 seed in the qualifying draw, earned spots in the main bracket. Odesnik advanced with a 7-6 (5), 6-4 win against Mischa Zverev of Germany. Joining him in the main draw are fellow Americans Steve Johnson and Rhyne Williams. Gastao Elias of Portugal is the other qualifier.
The top four seeds in the singles draw will be in action for a full slate of matches Tuesday.