Velasquez (13-1) defended the title for the second consecutive time, becoming just the fourth fighter ever to do so in the process.
His only professional defeat was a first round knockout loss to dos Santos in November 2011, who falls to 16-3 for his career.
"[The game plan] was the same as the last fight," said Velasquez.
"Pressure, but throw better punches. Crisper punches, so I could beat him to the punch. He has great heart."
The result was almost a virtual repeat of their match in December, with Velasquez able to bloody dos Santos from start to finish, despite being briefly staggered by his opponent early in the fight.
Dos Santos struggled with positioning in the cage, leaving him little space to land his notoriously powerful punches.
A straight right hand by Velasquez dropped dos Santos in the third round. Although the Brazilian managed to recover, he suffered a cut over his left eye which twice required medical attention.
"He's very -- what can I say? He beat me up," dos Santos said.
Similar to the display of heart he showed in the second fight, dos Santos willed himself to throw dangerous punches even in the later rounds. He backed Velasquez off in the fourth with a left elbow from the cage, but Velasquez was never troubled
In the end his aggression was his undoing. After attempting a standing choke on Velasquez which was violently countered by his opponent, dos Santos remained on his knees. Velasquez moved in with punches and referee Herb Dean had no choice but to stop the fight at the 3:09 mark.
UFC president Dana White was quick to praise heavyweight champion Velasquez, saying he fought the perfect fight.
“He said it before the fight: when Junior thinks I’m going to box, I’m going to wrestle. When Junior thinks I’m going to wrestle, I’m going to box,” said White.
Velasquez insisted that even though he won their second meeting, he had no choice but to get better or get left behind.
“He got better as well,” said Velasquez (13-1), adding that having an opponent pushing him so hard “ups all of the competition.”