Periodontitis is an oral immunoinflammatory disease, and macrophages play a crucial role in its pathophysiology. However, macrophage death during antibacterial activities will exacerbate inflammation and tissue damage. Porphyromonas gingivalis is a major constituent of subgingival biofilm plaques in periodontitis, but the effects and precise molecular mechanisms by which it triggers macrophage death remain unknown. Here we found that P. gingivalis infection notably activated multiple death pathways in bone-marrow-derived macrophages, including pyroptosis, apoptosis and necrosis. Furthermore, using RNA sequencing, we identified that P. gingivalis infection markedly increased the expression of Z-DNA binding protein 1 (Zbp1) in bone-marrow-derived macrophages. Initially identified as an interferon-induced tumor-associated protein, Zbp1 serves as an upstream sensor that regulates cell death by activating PANoptosis. Mechanistically, P. gingivalis induced a mitochondrial stress response, prompting the release of mitochondrial DNA. This mitochondrial DNA then interacted with Zbp1, consequently augmenting its downstream PANoptosis signals. In addition, P. gingivalis stimulated macrophage Zbp1 expression through the Tlr2/4-JNK-Stat3/5 pathway, exacerbating macrophage death. Importantly, blocking the biosynthesis of endogenous Zbp1 by pharmacological delivery with microneedles improved the survival of P. gingivalis-infected macrophages and inhibited periodontal tissue destruction. These findings highlight Zbp1 as a potential therapeutic target for P. gingivalis-induced periodontitis.