No wonder the injury hit Djokovic uttered to reporters afterward: "For me it felt like (the) first match I ever played on the tour".
While Federer completed a rain affected win over Argentine Federico Delbonis 6-3 7-6 (8-6) in his opener, Del Potro began his tournament by thumping promising Australian Alex de Minaur 6-2 6-1.
Novak Djokovic suffered a shock defeat by world number 109 Taro Daniel of Japan as he was knocked out of the BNP Paribas Open at Indian Wells.
His title defense got off to a soggy start Saturday night when play was suspended because of rain showers, with Federer up a set and tied 2-2 in the second.
Djokovic is making a cautious return to the ATP Tour after stopping his 2017 season following Wimbledon due to a right elbow injury.
The Indian Bhambri will meet 18th-seeded Sam Querrey in the third round after the big-serving American accounted for Germany's Mischa Zverev 6-4 7-5.
He lost to Chung Hyeon in the Australian Open fourth round in January before undergoing the surgery. "But at the same time, I just didn't feel good at all", he added. Very weird. I completely lost rhythm.
Federico was off to a better start in set number two, holding easily in the opening two service games to be leveled at 2-2 before the rain started to fall, forcing the organizers to call it a day and move the match into Sunday's program.
The defeat was just the fifth time in the past decade former world number one Djokovic has lost against a player outside the top 100 players in the world.
"It is still early stages for Novak coming back and the first one after surgery".
"Unfortunately I have to pull out", Nishikori said.
The five-time Indian Wells champion regained his composure and the momentum by breaking for a 4-3 lead in the second, only to again struggle to get the job done.
He extended his 2018 win streak to 13 matches and has only dropped three sets from 34 played this year.
If anyone knows what it is like to deal with injuries, it's Juan Martin del Potro - the career of the 2009 US Open victor has been ravaged by wrist injuries.