The 28-year-old, son of renowned former world champion Kostya Tszyu, was brilliant and brutal in the 12-round battle on Australia's Gold Coast that left Mendoza bloodied but somehow still standing.
All three judges scored the bout in his favour, 116-111, 116-112 and 117-111.
"He's world-class for a reason," Tszyu said of the Las Vegas-based Mendoza, who earned his right to face Tszyu with crushing upset knockout wins over Jeison Rosario and the highly-touted Sebastian Fundora.
"But he's second best."
The victory improved the Australian to 24-0-0, with 17 knockouts, and cemented his status as the number one challenger to big-talking American Charlo, who holds the other three major sanctioning body world crowns - WBA, WBC, and IBF - in the 154-pound division.
Tszyu won the WBO interim title when he stopped American Tony Harrison in March and defended it with a spectacular first-round demolition of Mexico's Carlos Ocampo in June to position himself as the mandatory challenger to Charlo.
But, instead of facing Tszyu as he was supposed to, Charlo opted to move up two weight classes to super middleweight and take on Canelo Alvarez in a more lucrative bout last month.
Charlo not only lost but was stripped of his WBO belt, with Tszyu elevated from interim titlist to full champion.
Delusional
"Charlo, where are you?," Tszyu said mockingly in the ring, tapping the belt he took from him. "He'll probably think in his delusional head that he would beat me.
"Come get it. Let's prove to everyone who is king of this division."
Charlo, who has taunted Tszyu as a "paper champion", has indicated he plans to return to the super welterweight division, with a fight between the two in Las Vegas seen as possible.
Against Mendoza, Tszyu was simply too powerful and precise.
After sizing each other up in round one, Tszyu got on the front foot, landing jabs to the face and body before the American had a better third round.
The patient Tszyu kept stalking Mendoza and a powerful left-right combination opened a cut on the American's nose. An uppercut in the fifth added a bloody nick under his swelling right eye.
The fight burst to life in the seventh with Mendoza doing well to stay on his feet as he was battered by blow after blow that left him on the ropes desperately defending.
A big right-hander hurt him again in the ninth and he was only saved by the bell in a brutal 10th, in serious trouble after a barrage of punches left him bloodied and stumbling.
More of the same was dealt out on the 11th but the American, who has never been knocked out, kept his feet and took it the distance after the doctor had a look and allowed the bout to continue.
On the undercard, undefeated Australian Sam Goodman won a unanimous points decision against former world title challenger Miguel Flores of Mexico in a 12-round featherweight fight.
Goodman, who is 16-0-0, is the mandatory challenger for the WBO junior featherweight title held by Japan's Naoya Inoue.
