Inflammatory responses can be of critical importance in determining both the course and outcome of infectious diseases. Buruli ulcer, a neglected tropical disease caused by Mycobacterium ulcerans (M. ulcerans), has been reported to induce both immunosuppressive and proinflammatory responses in the skin. Here, we found that genetic inactivation of the orphan receptor GPR84 in mice leads to spontaneous healing of ulcerative lesions, recapitulating the rare spontaneous healing observed in human Buruli ulcer. Mechanistically, M. ulcerans infection induced Gpr84 expression through Toll-like receptor 2 engagement, promoting proinflammatory cytokine release through a self-amplifying loop that sustained receptor expression and inflammatory signaling. Moreover, pharmacological inhibition of GPR84 with the antagonist PBI-4050, in combination with antibiotics, accelerated tissue repair in infected GPR84-competent mice, which was associated with attenuation of inflammatory responses. Together, these findings establish GPR84 as a promising target for host-directed therapeutic interventions in Buruli ulcer and its expression as a potential biomarker of lesion activity.