The unbeaten Mares (25-0-1) went on relentless attack to snap his opponent's decade-long winning streak with a unanimous win on points.
Mares never let the awkward Moreno find his rhythm and got to him in the fifth round, the man from Panama falling to the canvas following a three-punch combination.
The duo appeared to ease off the pace into the second half of the fight and that suited Mares, who finished strongly to impress the judges who scored it 116-110 (twice) and 120-106.
Moreno is now likely to step back down to bantamweight, where he still holds the WBA title, while Mares is looking for a unification fight with WBO belt holder Nonito Donaire next year.
"I could tell he felt my power and aggression," said the California-based Mexican. "He did take advantage when I waited too long, but he's a super champion and he gave me hell.
"I couldn't let him get comfortable with his style, because he's very good.
"I want to fight Nonito Donaire. That's the only guy to fight. We want to fight the best."
On the same bill at the Staples Center, Leo Santa Cruz retained his IBF bantamweight strap with an impressive ninth-round stoppage of fellow Mexican Victor Zaleta.
The latter went down to a left hook in the fourth and again to a combination in the seventh, and although Zaleta kept pressing the fight Santa Cruz (22-0-1) closed it out with a crushing right hand that saw the referee step in.