Jaron Ennis stopped Eimantas Stanionis at the Boardwalk Hall in Atlantic City to unify the IBF and WBA welterweight world championships.
Stanionis' corner pulled him out after the sixth round with the Lithuanian hurt after a knockdown.
Ennis forced Stanionis to the ropes and sent him down to one knee with a sequence of uppercuts and body shots.
"I was just picking it up. I knew he was going to go, from the second round, from certain things he was doing," Ennis said.
It was the first loss Stanionis had taken in his professional career.
"When I fight top-of-the-line guys, good guys, that's what you're going to see," Ennis said. "You're going to see a whole different me. When I'm in the ring, I'm in my happy place. When I've got a top guy and I'm fighting for something, it's a whole different story. Can't nobody mess with me.
"Everything's falling in line. It's perfect timing."
The 27-year-old Ennis is now unbeaten in 34 pro fights, finishing 30 of them inside the distance.
With that victory, Ennis could look for further unification fights next. Brian Norman holds the WBO championship at 147lbs with Mario Barrios the WBC belt-holder.
"I'd beat anybody in the world," Ennis declared. "I'm the best fighter in the world. I keep saying - these fighters can't mess with me."
Watch Ben Whittaker vs Liam Cameron 2 on Sunday April 20 live on Sky Sports.
