The match, which lasted 2 hours, 23 minutes, was Isner's fifth at the tournament after he won through three rounds of qualifying to reach the main draw. Four of those have gone three sets.
Isner fired 17 aces in 17 service games, bringing his total in his last two matches to 29, to edge his more experienced opponent in the longest match at the tournament to date.
The 144-ranked Isner also saved nine of 11 break points and converted three of five to clinch his first meeting with the 47th-ranked Ginepri.
Earlier, sixth-seeded American Sam Querrey beat qualifier Gilles Muller of Luxembourg 3-6, 6-3, 6-4 to book his quarterfinals spot.
Querrey, who also relied on a heavy serve for dominance producing nine aces, showed frustration at a lack of precision in other parts of his game.
"I thought I served really well and played well on the break points, but I didn't volley that well and got a little bit frustrated,'' Querrey said.
"I usually don't mind playing similar players, but I find it a bit difficult against lefties because of the way the serve swings.''
Top-seeded Argentine Juan Martin Del Potro overcame a rusty start to his first singles match of 2009 to beat Ernests Gulbis 4-6, 6-4, 6-1.
World No. 9 Del Potro was handed a bye to the second round and struggled to find his rhythm in hot conditions before settling in to beat the 51-ranked Latvian in 1 hour, 42 minutes.
Below-Par Barcelona Beat Real Mallorca
Serena Williams, Safina advance to quarterfinals
American qualifiers reach Heineken Open 2nd round
Athletic Bilbao Beat Below-Par Atlético Madrid
