The Argentine looked weary in the early stages of his clash with the Japanese, however he was not required to expand too much energy on a warm afternoon.
The Indian Wells champion is the favourite to complete a famous Sunshine Double next weekend – and his potential path to a 23rd title looks relatively smooth.
Nishikori, on the comeback trail after a difficult nine months, appeared well short of match sharpness. His progress was delayed by a recent illness – picked up in Indian Wells – and he struggled to cap the unforced-errors against the form player on the ATP tour.
It will take the former world No.4 time to find his groove again, but he is certain to start the upcoming clay-court season unseeded.
The match never produced the excitement the expectant crowd on Stadium Court hoped for, but the vast majority were delighted with the eventual outcome.
Nishikori slammed a forehand into the net to fall 3-2 behind in the first set – and it was strictly one-way traffic from that point onwards.
Del Potro will challenge Filip Krajinovic for a spot in the quarter-finals. The Serbian took out Novak Djokovic’s conqueror, Benoit Paire, 6-3 6-3.
Earlier in the day, Hyeon Chung thrashed qualifier, Michael Mmoh, 6-1 6-1 in just 62 minutes. He’s joined in the last sixteen by Joao Sousa, who overcame Jared Donaldson 1-6 6-3 6-4.
Marin Cilic edged Vasek Pospisil 7-5 7-6(4) and will take on either John Isner or Mikhail Youzhny on Tuesday.