Federer wowed a boisterous, capacity crowd at Crandon Park, winning 6-3 6-4 in just over 80 minutes of nearly flawless tennis.
Former U.S. Open champion del Potro, buoyed by a large Argentine contingent who did their best to lift him with regular chants of 'ole, ole, ole', did not submit easily but one break in each set was enough for Federer to move on to the fourth round.
Federer improved his career record against del Potro to 16-5, the Swiss closing out the match in style with a forehand winner before acknowledging the roaring crowd.
The 35-year-old, who missed the second half of 2016 with a knee injury, has lost only once this year, to Russian Evgeny Donskoy in early February.
An 18th grand slam crown in a five-set thriller over long-time rival Rafa Nadal at the Australian Open in January has been the highlight of the still young season, but the past two weeks in the United States have been second to none.
He ripped through the field at Indian Wells without dropping a set en route to the title, and has not lost a set in his first two matches in Miami either.
Federer is giving his opponents less time than ever to react, running them ragged by regularly standing inside the baseline and taking the ball early.
Next up for Federer is Spanish 14th seed Roberto Bautista Agut, who overcame a slow start to outlast American 22nd seed Sam Querrey 3-6 6-2 6-3.
Czech 10th seed Tomas Berdych beat 24th seed Gilles Muller of Luxembourg 6-3 6-4, while Adrian Mannarino of France edged Croatian Borna Coric 6-4 2-6 7-6(3).
(Reporting by Andrew Both in Cary, North Carolina. Editing by Steve Keating.)