The 28-year-old Williams, the tournament's third seed, was pushed to a first-set tiebreaker, but dominated the match the rest of the way. The scores were 7-6 (7-1), 6-2.
Williams walked away with a $95,500 first-place check and improved her career record to 506-121.
"I knew going into the final she was playing well," Williams told reporters.
When the latest world rankings are released Monday, she will assume a comfortable lead over Vera Zvonareva and Agnieszka Radwanska in the battle for the last two qualifying spots at the season-ending WTA Championships in Doha, Qatar.
Pennetta, 26, committed four double-faults and did not break Williams' serve.
She had reached the final with earlier wins against reigning world No. 1 and U.S. Open runner-up Jelena Jankovic in the second round and Spain's Anabel Medina Garrigues in the semis.
Swim Week Miami Beach 2014 [PHOTOS]