Argentine Del Potro, who won his only grand slam at Flushing Meadows in 2009, beat the 74th-ranked Spaniard 6-3 6-7(5) 6-4 7-6(7) on his fourth match point.
"Felt good because I won the big battle for the first round," Del Potro said. "He's a very tough opponent. He plays so solid on the baseline. He made a good forehands, backhands.
"We play like every time long rallies. I (had) to make three or four winners in the same point to win the point."
The match included a bad-tempered exchange between the towering sixth seed and the inspired Garcia-Lopez as the players bickered on a changeover when Del Potro questioned whether the Spaniard was entitled to treatment on his left leg.
Garcia-Lopez, who ended up on the losing end of several extremely close calls, later kicked at his towel in disgust after a replay of a point was ordered in the tiebreaker that he thought should have been ruled in his favour.
"I'm proud of the way I played, but I am a little bit disappointed because I gave everything, physically and mentally," the Spaniard said.
The four hour, 13 minute marathon actually lasted twice as long with two rain delays totalling more than four hours.
Despite the long day spent at the National Tennis Center, Del Potro said he was happy to be back in New York.
"As everybody knows it's my favourite tournament," Del Potro, who ended Roger Federer's streak of five straight U.S. Open titles in their five-set final, said in an on-court interview.
"This court means a lot for me after winning 2009. I'm trying to be ready for the two weeks. I pass a good, tough opponent tonight and I'm looking forward to my second round."
Del Potro will next play 2001 champion Lleyton Hewitt, who beat American wild card Brian Baker 6-3 4-6 6-3 6-4.
Garcia-Lopez, a 30-year-old veteran who entered with a 26-36 grand slam record, raised his game against Del Potro, showing great energy in running down the booming forehands launched by the Argentine, while whistling top spin groundstokes himself.
Still, Del Potro, winner of their only previous match six years ago in Paris, had the upper hand and struck 52 winners.
"I feel good with my level," said Del Potro, who waged the longest semi-final ever at Wimbledon this year in losing a tight five-setter to Novak Djokovic.
"My forehand was good. My serve improved since the last tournament. That's important."
(Reporting by Larry Fine; editing by Nick Mulvenney / Ian Ransom)
