Lomachenko shook it off and finished crisply after the break, ending it with a right hand that dropped Crolla face-first onto the canvas with an apparently broken nose.
In addition, this was his first title defense for the WBO belt.
"I would like to fight with Mikey Garcia", Lomachenko said, but the politics of boxing make that a hard bout to put together.
"I want to shock the world and beating him would be one of the biggest upsets of all time", he said.
Lomachenko has now won 12 straight bouts. Both Lomachenko and the California commission members thought the fight had been stopped and began to celebrate and enter the ring until Reiss restored order. He stayed there for some time but even when he was helped to his feet his camp still had to support his wobbly legs.
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Lomachenko then showed why it was a bad idea for Crolla (34-7-3), whose toughness wasn't enough.
The defending champion wanted a unification fight against fellow world champion, Richard Commey, but Commey suffered a hand injury when winning his title earlier this year, opening the door for Crolla.
The Ukrainian delivered a devastating knock-out in the fourth round at the Staples Center in Los Angeles to continue his remarkable legacy as the pound-for-pound star of the sport. The fight was promoted by Top Rank Boxing and aired live on the Worldwide Leader in Sports' digital streaming service, ESPN+. He fought for a world title in just his second professional fight and is the fastest fighter in history to become a three division world champion. It was mostly in vain as the champion controlled the pace and intensity of the bout, fighting on his terms and ultimately wearing Crolla down.
This was Crolla's second fight in the United States.