Nadal bested del Potro 4-6 6-3 6-4 for his third title since returning from a eight-month absence due to a sore left knee.
The 11-time Grand Slam champion notched his 53rd career win and first on a hard court since the 2010 U.S. Open.
His Indian Wells triumph -- which marked his 600th career match win -- came after earlier clay-court titles in Brazil and Mexico following his injury layoff.
Nadal improved to 17-1 for the best start of his career and has reeled off 14 straight wins.
It was an emotional victory for Nadal, who celebrated by falling to his knees by the net after shaking hands with his opponent.