Bee venom, which serves as a weapon to defend the colony from predator attacks, induces an immediate local inflammatory response that causes acute redness and swelling at the site of the sting. This venom-induced inflammation is a rapid anti-predatory defense strategy of the bee against vertebrate predators. Although acute inflammation by venom from venomous arthropods, including bees, is a typical response, how venom acutely elicits inflammatory responses remains unknown. Here, we identify a novel mechanism underlying acute inflammation and provide a rationale for the presence of superoxide dismutase (SOD3) in bee venom. In mouse models, paradoxically, SOD3 in bee venom (bvSOD3) acts as a reactive oxygen species (ROS)-based harm-inducing system to promote acute inflammation. Exogenous bvSOD3 rapidly induced overproduction of H2O2 through endogenously produced superoxide by venom components, such as melittin and phospholipase A2 (PLA2), which then upregulated the expression of proinflammatory genes and promoted the acute inflammatory response. Furthermore, a more severe noxious effect by bvSOD3 elevated a type 2 immune response, and bvSOD3 immunization protected against bvSOD3-mediated toxicity. Our findings that bvSOD3 promotes an acute inflammatory response and induces a protective immune response against inflammation may offer a new approach in venom therapy/immunotherapy.