The combination of DNA damage response inhibitors (DDR inhibitors) has emerged as a promising strategy for anticancer therapy. Herein, we demonstrate that the combined administration of poly (ADP-ribose) polymerase (PARP) and ataxia telangiectasia and Rad3-related (ATR) inhibitors elicits PANoptosis across diverse cellular lineages, including non-cancerous cell populations. The induction of PANoptosis is dependent on mitotic entry and ZBP1-dependent PANoptosome (ZBP1-RIPK1-Caspase8-Caspase6). We identify the Aurora kinase B (AURKB) as the upstream regulator, essential for phosphorylation of ZBP1 which impacts ZBP1-dependent PANoptosome assembly and activation. The Trp53^-/- Brca1^-/- model of ID8 and two patient-derived xenograft (PDX) models further confirm the occurrence of PANoptosis following combination administration in vivo. The toxicity is mitigated in ZBP1-knockout mice. This study unveils a mechanism that dictates cell fate during DDR inhibitors-induced aberrant mitosis, emphasizing the critical balance between efficacy and safety in optimizing DDR inhibitors combination therapies.