Nadal's milestone outing did not go according to plan early, condemned to a bagel for just the 14th time in his illustrious career, but the former world number one kept his composure to win 0-6 6-2 6-3.
The fifth seed - who boasted a superior 13-1 head-to-head record - was sensationally shut out in just 25 minutes in the opening set before halting Kohlschreiber in his tracks.
Next up for Nadal is Nicolas Mahut as he seeks his maiden title at the ATP 1000 event in Miami after reaching the final on four occasions without success.
— Miami Open (@MiamiOpen) March 26, 2017
Nadal did not look like a 14-time grand-slam winner from the outset, such was Kohlschreiber's dominance and the ease in which he had his way.
Kohlschreiber - the 26th seed - stormed out of the blocks, breaking in the opening game of the match as Nadal struggled to cope with the German's aggression.
While Kohlschreiber - who fended off a pair of break points in the second game - covered the court with ease and precision, Nadal struggled to read his opponent, tallying an uncharacteristic amount of shanked shots.
It got no better for Nadal, who did not hold serve in a lopsided first set as he won a woeful five of 15 points on his first serve.
Kohlschreiber won 18 of 26 points of 1-4 shots, wrapping up the first set in just 25 minutes, but Nadal emerged a changed man in the second.
Nadal was able to rectify his serve and rhythm to hold for the very first time in the opening game.
He had the chance to earn a 3-1 lead but Kohlschreiber showed he can produce in tight situations, saving a break point to level proceedings.
But Kohlschreiber - who recorded 18 unforced errors having only managed five in the first - finally stumbled, broken in the sixth game as a rejuvenated Nadal pulled clear to force a third set and strip the former of all his momentum.
There was only going to be one winner when Nadal levelled the match as Kohlschreiber went off the boil, serving out the match to love, with Mahut now standing in the way of the Spaniard and a quarter-final berth.
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