The world number one was untroubled from the outset, racing to a 4-0 lead before breaking Hewitt for the third time to take the opening set.
And Nadal broke again in the eighth game of the second set, before serving out the 6-1 6-3 victory.
Hewitt's career record against world number ones dropped to 0-18 with the loss.
Next for Nadal at the ATP 1000 hard-court event is Uzbekistan's Denis Istomin, who got the better of Russian 29th seed Dmitry Tursunov 6-7 (8-10) 6-0 6-3.
Third seed Stanislas Wawrinka also progressed but was tested in the second two sets by Daniel Gimeno-Traver of Spain before winning 6-0 3-6 6-3.
The major upsets of the day belonged to Edouard Roger-Vasselin, Roberto Bautista-Agut and Guillermo Garcia-Lopez.
Roger-Vasselin, of France, dumped Croatia's 25th seed Marin Cilic 6-2 7-6 (7-5) from the tournament, while Spaniard Bautista-Agut thrashed Polish 19th seed Jerzy Janowicz 6-4 6-1.
Garca-Lopez trumped French 23rd seed Gael Monfils 6-2 7-5, while lucky losers Dusan Lajovic and Benjamin Becker also made the most of last-minute call-ups.
Lajovic, of Serbia, defeated Taipei's Yen-Hsun Lu 6-1 6-7 (3-7) 6-3, while Germany's Becker edged out American Ryan Harrison 7-5 3-6 7-6 (7-2).
Lajovic came in for Tommy Haas (shoulder), while Becker replaced Juan Martin del Potro (wrist).
French 26th seed Gilles Simon bowed out, as Portugal's Joao Sousa earned a third-round berth with a 7-6 (7-5) 3-6 6-3 triumph.
That result opens up the draw for Czech seventh seed Tomas Berdych, who was a 7-6 (7-5) 6-1 victor over France's Stephane Robert.
Ukraine's 22nd seed Alexandr Dolgopolov continued his run of form, with a 6-4 6-2 victory over Finland's Jarkko Nieminen.
John Isner won an all-American battle with Donald Young, with the big serving 10th seed triumphant 6-7 (5-7) 6-3 6-4.
Spain's Nicolas Almagro - the 18th seed - surpassed Sam Querrey 6-4 6-4, while Italian Fabio Fognini beat Slovakia's Lukas Lacko by the same scoreline.
Joining Querrey among the American casualties was Jack Sock, with the qualifier going down to Canadian 12th seed Milos Raonic 6-4 7-6 (7-1).
Rafael Nadal crushes Lleyton Hewitt in Miami
