The top seed needed treatment three times but still went on to win 6-4 7-6 (7-3) 6-1.
“It was definitely affecting my serve and my backhand,” said Djokovic, who lost his serve five times.
The Serb added he had not felt that “kind of sensation too many times” in his career.
“I didn’t know if I would be able to finish the match. I’m really glad I have,” he said.
Fellow Serb Dusan Lajovic will be Djokovic’s next opponent if he beats American Denis Kudla.
Their meeting was one of the many second-round matches cancelled on Wednesday after rain decimated play in New York.
Only the eight matches played underneath the closed roofs on Arthur Ashe Stadium – where 16-time Grand Slam champion Djokovic beat Londero in the first match of the night session – and Louis Armstrong Stadium survived the drizzle which fell for the majority of the third day.
Djokovic, 32, is favourite to win his fourth title at Flushing Meadows after winning four of the past five Grand Slams, yet the sight of him needing intense massages in his second-round match may provide hope to his rivals that the Serb is not invincible.
Djokovic asked for a first medical timeout immediately before breaking back for 3-3 in the first set, calling the trainer again moments after he clinched the opener by outlasting Londero in a 22-shot rally.
Londero, who had never played in the main draw at Flushing Meadows until this tournament, managed to take advantage in a fluctuating second set where he led 3-0 and trailed 5-3 before forcing a tie-break.
However, Djokovic upped the intensity to dominate the second-set decider and encountered few problems from then on.(Theguardian)
