On a hot, humid night at Flushing Meadows, Djokovic waged an entertaining battle with the 33-year-old serve-and-volleyer, before finishing off the 18th seed 7-2 in the fourth set tiebreaker to complete a 6-1 3-6 6-3 7-6(2) victory.
Lopez won 28-of-41 serve-and-volley points, while Djokovic countered with 33 forays to the net that produced 19 points for the world number one.
"He's one of the rare players who actually serves and volleys after the first and second serves," said Djokovic, winner of this year's Australian Open and Wimbledon championships. "He's got a very big serve."
Lopez served up 14 aces, while Dojokovic registered nine.
"It was anybody's game in the fourth set," the Serb said. "I'm just glad to get through in four."
Djokovic had beaten Lopez in their five previous meetings but the lefty was confident, coming off a Cincinnati hardcourt event where he reached the quarters with wins over Milos Raonic and Rafa Nadal before losing to world number two Roger Federer.
"My game plan was to be aggressive," Lopez said. "He was having some trouble reading my serve.
"The match from my side was great. I have to be satisfied with the match I played with the number one player in the world. I couldn't do any better today. He just was better in the tiebreaker in the fourth. I think I played a great match."
Djokovic, 61-5 with six tournament titles this season, will face defending champion Marin Cilic of Croatia in the semi-finals. The ninth-seeded Cilic advanced with a five-set win over France's Jo-Wilfried Tsonga.
Nine-times grand slam winner Djokovic reached his ninth successive U.S. Open semi-finals and the 2011 champion expects another challenging match against Cilic, despite owning a 13-0 record against him.
"He hasn't lost a match (here), 12 matches in a row, so I'm sure he feels confident," Djokovic said. "I know him very well. I have played him many, many times. We are great friends.
"I know what to do and I'm hoping I can execute the game plan."
(Editing by Amlan Chakraborty/John O'Brien)
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