UFC fans went into the show at Phoenix expecting a close main event.
Velasquez, widely recognised as the company's best ever heavyweight, was a marginal favourite against the dangerous Ngannou.
But Cain found himself blown away in 26 seconds.
The former champ appeared to damage his knee, which led to him being finished off by Ngannou.
Velasquez was seen limping out of the Octagon after the fight.
Fans tuning in for the main event labelled it a "massive letdown".
One wrote: "It's over in 26 seconds, what a letdown."
Another wrote: "Ngannou didn’t even hurt Velasquez, somehow Velasquez hurt himself. The man has the worst luck. That was sad to see."
And one UFC fan even wrote: "Francis Ngannou just slaughtered Cain Velasquez."
Velasquez apologised to fans after the fight in Phoenix, Arizone.
Velasquez had been linked with a move to the WWE before the bout, and his convincing loss may have made up his mind.
When asked of he was interested in the move, he said: "“Hell yeah. I am. The transition was pretty easy. I’m pretty athletic for a big guy. I learn by watching."