Any questions marks regarding his 2006 split decision win over the Hawaiian was put to an end.
"Last time I fought him I won a decision," St-Pierre said. "This time I really wanted to take him out and I'm glad that I did it."
St-Pierre said he accomplished his goal of preventing Penn's boxing by utilizing a wrestling game to stiffen Penn's shoulders.
"BJ Penn is a world champion in Brazilian Jiu-Jitsu," St-Pierre said. "My strategy in the first two rounds [was] to make a wrestling match with him because he's got really quick hands and his shoulder is made for boxing."
Although Penn was able to defend St-Pierre's takedown attempts the first, the lightweight champ was put on his back in the second and fared progressively worse with each round.
Controlling the fight on the ground with punches and elbows, St-Pierre overwhelmed Penn through four rounds. On the scorecards for the four rounds, St-Pierre was given two 10-8 rounds by two of the judges and one 10-8 round from the third.
Between the doctor, referee Herb Dean and Penn's corner, the fight was unanimously called off.
St-Pierre wins his fifth straight to go 18-2 in his career while Penn falls to 13-5-1.
With Penn out of the way, Thiago Alves is next for St-Pierre.
"I'm a world champion, and a proud champion and I want to fight the best guys in the sport, and I think Thiago is next," St-Pierre said. "He's a fighter I have a lot of respect for, so it's going to be a good fight."
Machida showed that he can be "elusive" while being aggressive at the same time. Machida avoided Silva's knockout power and outstruck Silva, dropping the American Top Team fighter twice before knocking him out.
"I'm ready [for a title shot], whatever, whenever, whoever, I'm here," said Machida, who was given a roaring approval for a title shot from the crowd.
Machida extends his undefeated record to 14-0 while handing Silva, 13-1, his first career loss.
1. Dan Cramer def. Matt Arroyo via split decision (29-28, 28-29, 29-28)
2. Jake O'Brien def. Christian Wellisch via split decision (28-29, 29-28, 29-28)
3. John Howard def. Chris Wilson via split decision (29-28, 28-29, 29-28)
4. Thiago Tavares def. Manny Gamburyan via unanimous decision (29-28, 29-28, 29-28)
5. Jon Fitch def. Akihiro Gono via unanimous decision (30-27, 30-27, 30-26)
6. Clay Guida def. Nate Diaz via split decision (28-29, 29-28, 29-28)
7. Karo Parisyan def. Dong Hyun Kim via split decision (29-28, 28-29, 29-28)
8. Jon Jones def. Stephan Bonnar via unanimous decision (30-27, 29-28, 29-28)
9. Lyoto Machida def. Thiago Silva via KO (punch) - R1 (4:59)
10. Georges St. Pierre def. BJ Penn via TKO (doctor/ref stoppage) - R4 (5:00)