Lopez has had his share of marathon duels, including his epic 2009 Australian Open thriller against Gilles Muller that went four hours and 22 minutes.
Monday's match lasted 94 minutes, but was a full three-set battle that saw Lopez recover from a slow start to triumph.
The sixth seeded Spaniard had his service broken twice and fell behind in the first set, but he would not be broken on his service for the remainder of the match as he found form and put away Querrey.
To help his cause, Querrey went backwards during a contest that saw him lose five games on his service and commit four double faults.
In earlier Delray action, Adrian Mannarino topped Jack Sock in straight sets 6-4 6-2.
Mannarino had fallen to the American Sock in their two other match-ups this season but broke through in a big way.
Despite Sock's seven aces, the Frenchman was able to pounce on Sock's second serve attempts and capitalize.
The other results filled out the four qualifying spots in the 32-player field that includes number one seed Tommy Haas of Germany.
Delray Beach International results
6-Feliciano Lopez (Spain) beat Sam Querrey (U.S.) 4-6 6-2 6-3
Adrian Mannarino (France) beat Jack Sock (U.S.) 6-4 6-2
Rio de Janeiro Open results
Thomaz Bellucci (Brazil) beat Santiago Giraldo (Colombia) 3-6 6-4 6-3
Federico Delbonis (Argentina) beat Guilherme Clezar (Brazil) 6-1 6-1
Facundo Bagnis (Argentina) beat Joao Souza (Brazil) 7-5 2-6 6-2
Dusan Lajovic (Serbia) beat Filippo Volandri (Italy) 6-7(7) 6-3 4-0 (Volandri retired)
Martin Klizan (Slovakia) beat Guillermo Garcia-Lopez (Spain) 6-4 4-6 7-6(4)