Del Potro always enjoys plenty of crowd support in Miami, which has a large Argentine community, and it was the same story again with chants of support ringing out for the 28-year-old on a packed Crandon Park center court crowd.
Federer was forced to save four break points in the first set, but he got ahead with a thundering forehand to take a 5-3 lead and served out for the set.
The Argentine had a chance to turn things around when he had a break point when down 4-3 in the second set but Federer, moving well and looking full of confidence, held firm and wrapped up the match in one hour and 22 minutes.
The Swiss, who claimed an 18th Grand Slam title at the Australian Open in January and won in Indian Wells earlier this month, will face 14th seeded Spaniard Roberto Bautista Agut in the next round.
Czech Tomas Berdych, Miami finalist in 2010, defeated Gilles Muller 6-3, 6-4.
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