The American world number 17 hit 39 champs to seal a 6-1 7-6 (7-2) triumph in one hour 22 minutes.
He hit 16 experts, won 83% of focuses on his first serve and took the primary set against the Argentine in 27 minutes.
Isner will meet German world number five Alexander Zverev after he beat Pablo Carreno Busta 7-6 (7-4), 6-2.
Previous US Open champion and world number six Del Potro guaranteed his lady Masters 1000 title in Indian Wells not long ago and has won 21 coordinates this season, the most on the ATP Tour.
"I am so glad," said 32-year-old Isner, offering for a first Masters 1000 title. "He is so drained and has played such huge numbers of amusements, and despite the fact that the primary set was speedy I knew it wouldn't resemble that in the second.
"I have played a great deal of enormous matches and not possessed the capacity to get such a decent begin - yet I am playing a portion of the best tennis I have played in such quite a while."
Fourth seeded Zverev took 88 minutes to beat Spain's Carreno Busta.
The 20-year-old is offering for a seventh vocation ATP title and first of the season when he faces Isner in the last.
"I didn't feel I was playing my best in the start of the main set, a considerable measure of mistakes," Zverev said.
"I was down in the tie-break and I resembled, I'm losing in any case I should be forceful. With the goal that's what I did, I hit a couple of champs. [I was] extremely lucky to win the main set."