The 14th seed added a second Miami title to the one she captured in 2005 - before retiring from the WTA for more than two years only to decide to launch a comeback in 2009.
Clijsters, who married and had a baby during her break from the tour, will climb to number 10 in the world rankings next week, the highest ranking for the former number one since her return to competition.
Her young daughter, Jada, was watching from the stands as the 26-year-old Clijsters wrapped up the victory in just 58 minutes, lifting her arms in triumph when Williams sailed a forehand long on the first of three-match points.
The title is her third since her comeback, which started with a bang last year with a US Open triumph.
Top-ranked Serena Williams sat in the photographers' pit and cheered her sister, but Venus couldn't get her game on track.
While Serena has been sidelined with a left knee injury since her Australian Open victory, Venus had been the hottest player on the WTA tour with 15 consecutive match wins and titles in Dubai and Acapulco last month.
But the third-seeded American, who won the prestigious Miami title in 1998, 1999 and 2001, finished with a total of 29 unforced errors and won only nine points in the second set.
Clijsters, brisk and aggressive, made the most of Williams' struggles.
She took a 3-1 lead in the first set, and cemented her grip on the match in the next game when Williams, up 40-15, went on to drop her serve with the aid of an overhead slammed into the net, two double faults and a netted volley.
Williams would win only two more games in the match.