The thrilling victory - lasting nearly three hours - secured a maiden Masters 1000 title for world number eight Del Potro and just his seventh win in 25 attempts against Federer.
Del Potro was tipped as a future world No. 1 in 2009 after the then 20-year-old reached the Australian Open quarter-finals and the French Open semi-finals before capturing his maiden Grand Slam at Flushing Meadows. However, Del Potro saved a remarkable three match points to take the third set into a tie-breaker before beating Federer for the seventh time in 25 meetings between the duo.
Federer faced break points in the opening game of the second set but an emphatic forehand forced deuce, before the Swiss served his way out of trouble. Margin = +45 points 5-9 Shots = 152 won / 130 lost.
"I lost my serve a little bit, and then he was clean and I wasn't", Federer explained. He handed Federer his first loss of the year, snapping the Swiss superstar's 17-match winning streak that was the best of his career. And I'm excited to keep working. He was also slow in reading Del Potro's game, right from the outset.
Federer's attention will need to switch quickly to the next event on the tour, the Miami Open, which begins on Wednesday. "It's unfortunate, but I'm happy for him".
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For all the camaraderie in the locker room, this was pure, intense competition and also a particularly fine tennis match, filled with winners on the run, drop shots and phenomenal fast-twitch defense from Federer as he repeatedly half-volleyed del Potro's huge shots from the baseline or closer to the net. (Having said that), Juan Martin well played today.
And Federer cut a forlorn figure in the eventual tie-break, which Del Potro won at a canter to become the first player from Argentina to reign supreme at Indian Wells.
Federer, the oldest world number one in ATP history at 36, entered the final having dropped just one set, in a hard semi-final test from Croatia's Borna Coric.
"But what's interesting is that he put himself out there with no double-hander nearly, but just happy to slice and still take losses, I guess, you know, because he knew it was going to probably not be enough against some players, but he was happy enough playing this way, which I admire a lot".
"I feel frustrated, you know, that I let an opportunity like this go by", Federer said.
"It was a lot of chances on either end", Federer said.