The couple, who have dated for more than 20 years, began to bicker openly after Behar showed a clip from their reality show Gene Simmons Family Jewels, wherein the 'God of Thunder' singer posed seductively with a pair of young women for a photograph.
As Behar prompted Simmons to defend his behaviour, Tweed said: "He's a pig and I don't like it. I'm done."
Simmons attempted to calm Tweed by crediting her with accepting his failures, which appeared to cause the model to grow more visibly upset.
After Simmons made a joke about his famed sexual history, Tweed slapped him on the shoulder and removed her microphone, saying as she walked off the set: "It's so rude of you to joke about [this]."
Behar questioned a seemingly stunned Simmons as to whether he is headed for a split, to which he replied: "I hope not."
The full Joy Behar Show interview airs tonight at 10pm ET on HLN, while Gene Simmons Family Jewels airs Tuesdays on A&E.
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Watch Shannon Tweed's abrupt exit from The Joy Behar Show below: