The former world champion won beat the American with scorecards of 115-113, 116-112 and 117-111 from the three judges.
The tallies, though, did not necessarily match up on what was a competitive bout at Madison Square Garden in New York.
Lomachenko returned to boxing after joining his country's war efforts against Russia's invasion, which forced him turn down a major title unification earlier this year.
But it was the taller Ortiz who started on the front foot in the first round, throwing a number of hard strikes from distance to give Lomachenko an early bruise under his right eye.
The American's intensity continued to stifle Lomachenko for a while until the Ukrainian southpaw started to work his way into the bout with some powerful shots to Ortiz's head.
The Ukrainian made sure he finished the final two rounds strongly. He surged onto the front foot, linking together combinations of punches and fighting furiously to the end.
Lomachenko started to assert control, combining his punches well toward the latter stages to ensure he finished strongly in the final two rounds.
"I'm happy, I'm happy to be back in the ring and make this great show," Lomachenko said after securing victory.
"He is a tough fighter, he is a good fighter."
Lomachenko has now set his sights on a bout with undisputed lightweight champion Devin Haney (23) - who was ringside in New York.