The 21-year-old Mein tagged Santos several times in the round, bloodying his face. He then drove him backwards with a punch to the liver and left to the head, finishing off with a dozen elbow strikes at the fence three minutes 18 seconds into the third round.
The fight was on the undercard of Strikeforce's Heavyweight Grand Prix at the U.S. Bank Arena.
The main card pitted Josh Barnett (27-5) against Russia's Sergei Kharitonov (18-4) and Daniel Cormier (8-0) against Brazil's Antonio (Bigfoot) Silva (16-2) in the tournament semifinals.
A relaxed Mein smiled as he was introduced. The heavily tattooed Santos just glowered and pounded his chest.
Santos connected with low kicks early. Mein returned the favour and used his reach to snap a few punches. But with 90 seconds left in the first round, a vicious Santos kick scvythed Mein down to the ground briefly.
Mein (23-7) changed fighting stances in the second round, possibly to protect his left lead leg from kicks. Santos (18-15) just started chopping away at the right leg. Mein began to put a few punches together as the round wore on.
In the third, Mein took control with his striking.
"He was kicking me hard and my legs were sore," said Mein. "So I stayed in the pocket and just kept picking away. I hit him with a nice body shot, that hurt him a little bit. Then the elbows to finish him."
In women's action, bantamweight Alexis Davis (11-4) of Port Colbourne, Ont., stopped Amanda (Lioness of the Ring) Nunes (6-2) at 4:53 of the second round.
The fight pitted a striker (Nunes) against a grappler (Davis) and Nunes came out swinging. Davis was game but was second best on the striking exchanges against Nunes, who stopped Victoria's Julia (The Jewell) Budd in 14 seconds last time out.
Davis took it to Nunes at the fence in the second round, looking to grind away in the clinch. And Davis got the mount when she reversed a takedown, punching away at a face-down Nunes until the referee Greg Franklin stepped in
Nunes had won six straight since losing her debut in March 2008.
Mein (pronounced Mee-IN) started fighting professionally at 16 with bouts coming quickly thanks to his father Lee Mein, a promoter and fighter in his own right.
Mein has now won six straight, stopping Dream champion Marius Zaromskis and former UFC fighters Josh Burkman and Joe Riggs along the way.
Santos was coming off a January loss to former Strikeforce champion Nick Diaz and is 4-6 in his last 10 fights. Prior to Diaz, the Brazilian beat Zaromskis.
The 33-year-old Santos is married to Strikeforce women's 145-pound champion Cris (Cyborg) Santos, who was in his corner Saturday.
In other undercard action, middleweight Dominique Steele (4-1) won a unanimous decision over Chris Mierzwiak (3-1).