Though the British world number three edged a close first set 7-5 on the tiebreak, he lost serve once in the second and three times in the third to make a premature exit from the ATP Masters 1000 event. Seventh-seeded Del Potro will next face world number one Novak Djokovic, who was barely tested as he demolished Jo-Wilfried Tsonga 6-3 6-1 earlier on Friday to extend his unbeaten run to 22 matches.
On a sweltering afternoon at Indian Wells, Murray saved two break points in the first game of the match but there were no further opportunities for either player as a closely contested opening set went into a tiebreak. A big forehand winner by the Scotsman earned him a 5-2 lead but he double-faulted and then netted a forehand, screaming to himself in disgust, as he let Del Potro pull back to 5-4. The Argentine then hit a backhand long for Murray to earn his first set point at 6-4 and, though he squandered that with a wayward backhand, he clinched the set at the next opportunity on a backhand error by his opponent. However, the Scot failed to take advantage and was broken to love in the second game of the second set after double-faulting.
Del Potro served out to level the match, clinching the set with a leaping overhead smash. Murray was again broken in the third game of the final set, after netting a forehand, and also in the fifth, after hitting a backhand long, to trail 1-4.
Unable to break the towering Argentine's serve, Murray's challenge faded quickly and the match ended after two hours 31 minutes when the Scotsman double-faulted for an eighth time.
Top seed Djokovic delivered a ruthless display against the eighth-seeded Frenchman Tsonga in the first match of the day, breaking his error-prone opponent twice in each set and not dropping a single point on his own serve in the second set.
"I definitely feel very happy about this performance today," Djokovic said courtside after improving his record for the season to 17-0. "I thought Jo didn't play his best. He made a lot of unforced errors and his serve wasn't going well and that made my life a lot easier on the court. "I really didn't care about how my opponent felt. I just tried to focus on the job I need to do, and my performance was really good."