Ortiz had pinned Mayweather against the ropes before he was penalised by referee Joe Cortez for a head-butt.
After a brief time-out, Ortiz apologised to his opponent in the centre of the ring by touching gloves and Mayweather suddenly responded with a left hook and crunching right that dropped Ortiz to the canvas.
Boos rang out from the crowd in the MGM Grand Garden Arena but Mayweather, who improved his career record to 42-0 with 26 knockouts, was unrepentant.
"I got hit with a dirty shot, I was protecting myself at all times," the 34-year-old said ringside. "I hit him with a left and then a right hand, and that ended the bout."
Asked to describe what happened as a replay of the final moments was shown on a giant television screen above the ring, Mayweather replied: "We touched gloves, right hand and that's all she wrote.
"You just protect yourself at all times. I was victorious. If he wants a re-match, he can get a re-match."
Mayweather then showered his interviewer with abuse and said he had never given him "a fair shake".
Fighting for the first time in 16 months, Mayweather had upped the pace early on in the fourth round with a flurry of body jabs and upper cuts.
Ortiz responded with a furious sequence of blows before pinning the challenger to the ropes.
Ortiz, who took the WBC welterweight title from Andre Berto in April with an unanimous points victory, slipped to 29-3-2 with 22 knockouts.
