The 33-year-old "Lollipop" hitmaker, a known weed advocate, was booked as the headliner for the High Times publication's Cannabis Concentrates Cup show in San Bernardino, hitting the stage after fellow hip-hop star B.O.B.
However, Wayne performed just four songs before vowing never to return to the drug-filled event, dropping the microphone as he made a quick exit, reported New York Daily News.
"Don't you ever, ever, ever ask me to do this again!" he fumed as he cut short his set.
Organisers at High Times have also been left stunned by Wayne's behaviour and have since issued a statement addressing the incident.
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It read: "We have no idea why, after a stellar performance by B.O.B, Lil Wayne suddenly ended his performance after just four songs when he was contractually committed to performing for an hour for the fans.
"We are truly baffled by why Lil Wayne would do this in front of thousands of Cannabis Cup attendees - in total disregard for his fans - and are awaiting an explanation from his team."