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The Mexican won 120-108 on two cards and 119-109 on the third.
Santa Cruz, 23, remained unbeaten after 20 bouts, with one drawn and 11 knockouts. He piled on points with an array of punches, notably his left hook to the body.
He set the tone in the opening round, getting right to work at a fast pace. Malinga, 32, stayed in front of Santa Cruz, but could not hurt the younger fighter.
The South African gradually slowed down and was hurt in the seventh by yet another left hook to the body, which the California-based Mexican followed up with a combination to the head.
Malinga refused to go away but couldn't find a way to turn the tide.
He had come into the bout after a 19-month layoff since a unanimous 12-round decision over Filipino Michael Domingo that earned him a title shot.
The title was vacated by Abner Mares, who stepped up in weight to take over the WBC super-bantamweight title.
Malinga fell to 20-4, with one draw after the bout, which took place in evening sunshine in an outdoor ring at the Home Depot Centre.
Santa Cruz had fought five times since Malinga last stepped into the ring. Malinga is the only boxer who has gone twelve rounds with him.
In his only other world title bout, Malinga was stopped in the first round by Japan's Hozumi Hasegawa in Kobe, Japan, in 2009.
