While the attractive couple certainly hasn't shied away from PDA in the past, the Fox soiree marks their first public appearance.
The happy couple was all smiles throughout the night, keeping close as they posed together for photographers.
The 52-year-old actor also introduced McHugh to his new Fox family, mingling with Darren Criss and his girlfriend, Mia Swier.
Stamos seemed to be the life of the party at the Comic-Con get together, later talking with fellow Scream Queens actor Taylor Lautner.
ET caught up with the cast of the hit comedy-horror show earlier that day, where Stamos couldn't help but crack a couple jokes about being the newest "eye candy" to join the series.
"Our first shot yesterday we came out of the elevator, they start on our shoes and they pan up," he told ET's Leanne Aguilera. "Then [executive producer] Brad [Falchuk] goes, 'John, could you grab yourself?'"