Williams struggled to keep the ball in play, and Clijsters completed the shockingly lopsided victory in 58 minutes.
When Williams hit one final errant forehand on match point, Clijsters raised her arms in triumph.
After retiring in 2007, Clijsters married and became a mother before returning to the tour last August. The title is her third since her comeback.
Williams repeatedly was bested from the baseline, where she won nine points to 37 for Clijsters. Williams won only nine points in the second set, when Clijsters' roll gave her a 4-love lead.
Top-ranked Serena Williams sat in the photographers' pit and shouted encouragement to her sister, but it failed to help. Of the 55 points Clijsters won, 30 came on unforced errors by Venus.
Serena has been sidelined with a left knee injury since winning the Australian Open two months ago. In her absence, Venus had been the hottest player on the tour with 15 consecutive wins, her longest streak since 2004.
Venus took the court for the final with her right thigh wrapped, as it had been for every previous match in the tournament. She also wore a wrap on her left knee for the first time, perhaps a sign of the wear from playing on hard courts.
Clijsters, who also won the Key Biscayne title in 2005, earned $700,000. She'll climb to 10th next week, the highest ranking for the former No. 1 since she returned to the tour.
Williams received $350,000.
