Silva (25-4) toyed with Griffin (16-6) for the few minutes they were in the cage before putting him away at 3:23.
Silva jumped on top of the padding around the octagon, threw his body back and roared in celebration. Griffin, who received a huge ovation to the ring, sprinted out before the decision was announced.
Silva twice knocked down Griffin and struck him with repeated blows to the face.
Matthew Riddle bloodied Dan Cramer to win by unanimous decision, and George Sotiropoulous made training partner George Roop submit on the undercard of UFC 101.
Riddle and Sotiropoulous helped usher in a new breed of Broad Street Bullies in Pennsylvania's first major mixed martial arts card in front of a ready and raucous crowd.
Most of the fighters on the five-bout undercard generally failed to deliver the punishing action the Philly crowd was dying to see. Fans were lined around the Wachovia Center about 90 minutes before the first prelim fight, and the arena was nearly packed when Danillo Villefort fought Jesse Lennox in the first match.
When the two danced around the mat on their barefeet in the opening 10 seconds, the frenzied crowd started booing as if the Flyers were eliminated from the playoffs.
"Every restaurant, everybody we bumped into in the streets, the media people here, they've all been fantastic," Ultimate Fighting Championship president Dana White said before the start of the main card. "Now I know why this place is the biggest fight town in America. This place is (pretty) awesome."
The stacked card has BJ Penn (13-5-1) defending his UFC lightweight crown against No. 1 contender Kenny Florian (13-3), and UFC middleweight champion Anderson Silva (24-4) fights Forrest Griffin (16-5) in the two main events later Saturday night.
White has actively worked at expanding UFC cards outside of Las Vegas, and got a huge break in February when the Pennsylvania State Athletic Commission legalized MMA.
Philly fans responded in a huge way, with more 17,000 fans attending in a city known more for its deep boxing roots than rooting on fighters in the octagon.
"There were 11,000 people here for the first fight (of the night). That's as many as Mandaly Bay can hold," a beaming White said. "Just awesome."
The crowd roared when Penn was shown on the videoscreen walking into the arena. Boxer Roy Jones Jr. had a front-row seat.
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