Porphyromonas gingivalis (P. gingivalis), a gram-negative anaerobic bacterium, is the most common cause of periodontitis. P. gingivalis secretes several virulence factors, such as gingipains, LPS, and OMVs, which potentially induce the release of inflammatory cytokines such as IL-1β, TNFα, and IL-6 through inflammasome activation and TLRs. Previous reports have suggested that the host inflammatory response to P. gingivalis infection induces the progression of autoimmune diseases, including multiple sclerosis. We demonstrated enhancement of NLRP3 inflammasome activation in macrophages by P. gingivalis infection under hypoxia with inducing ROS. We also found that HIF-1α regulated by TRIF triggered exacerbation of inflammasome activation by P. gingivalis under hypoxia. Moreover, HIF-1α deficiency in myeloid cells recovered the progression of neurological symptoms in a mouse model of multiple sclerosis with P. gingivalis infection, including IL-1β and IL-17 production in the spleen. In this study, we showed that hypoxia controls inflammasome activation induced by periodontitis-associated bacterial infection, resulting in the progression of autoimmune diseases.