Flores won 98-92, 98-92 and 99-91 on the David Benavidez-Gilberto Ramirez undercard in Las Vegas, handing Mexico's Lucero his first defeat.
The Argentine underdog took control early and dominated the second half, badly hurting Lucero with combinations and outlanding him 214-99 in power punches through eight rounds.
The result reversed the picture from earlier in the fight, when Lucero had taken Round 4 but still trailed 39-37, and boosted Flores' profile on an international stage.
After a dominant start, can Ismael Flores survive Lucero's surge and spoil the undefeated prospect's U.S. takeover?
Can Isaac Lucero's stunning Round 4 rally fuel a comeback victory in his high-stakes U.S. debut?