On the men's side, qualifier Guillermo Canas, who last week ended world number one Roger Federer's 41-match winning streak, beat experienced Briton Tim Henman 3-6, 6-2, 6-1.
Williams, playing for the first time since winning in Memphis last month, produced 31 unforced errors in the first set before overwhelming her 88th-ranked opponent.
"At four-love I was thinking hold, break, hold, it's even," Williams told reporters. I felt really confident.
"I didn't feel like it was a set for me to lose. It was definitely a set I could win, just keep some balls in."
The American improved to 34-5 at the tournament which she won in 1998, 1999 and 2001.
Top seed Maria Sharapova will begin her campaign against 93rd-ranked Yung-Jan Chan of Taiwan who beat Nuria Llagostera Vives of Spain 6-2, 6-3.
Sharapova, last year's runner-up at Crandon Park to fellow Russian Svetlana Kuznetsova, lost in the fourth round of the Pacific Life Open last week.
In other first-round matches, Dutch teenager Michaella Krajicek, beaten last week by Sharapova, advanced to face Czech eighth seed Nicole Vaidisova with a win over Georgian Anna Tatishvili 6-3, 7-6.
Frenchwoman Emilie Loit knocked out last week's surprise package Sybille Bammer of Austria 2-6, 6-3, 6-1.
Austrian Bammer, the only mother in the world's top 50, beat former world number one Serena Williams in Hobart this year and lost in the Pacific Life semi-finals to Kuznetsova.
Argentine former world number eight Canas continued his comeback after serving a drugs ban by handing Henman his third defeat in a row.
Henman, 32, was playing in Miami for the 12th year in a row and reached the 1998 semi-finals. He was competing in only his third event of the season after overcoming a knee injury.
American Vince Spadea defeated compatriot Robby Ginepri 6-1, 6-3 and Frenchman Sebastien Grosjean eliminated former French Open runner-up Martin Verkerk of the Netherlands 6-3, 6-4.
Two Americans advanced, youngster Sam Querrey beating Russian Igor Andreev 5-7, 6-2, 6-4 and Kevin Kim ousting German Benjamin Becker 6-4, 3-6, 6-2.