Multidrug-resistant Acinetobacter baumannii, a common pathogen responsible for nosocomial infections, is the main causefor outbreaks of infectious diseases, such as pneumonia, meningitis, and bacteremia, especially among critically ill patients.Epidemic A. baumannii is a growing public health concern as it is resistant to all existing antimicrobial agents, therebynecessitating the development of new therapeutic approaches to mount an effective immune response against this bacterialpathogen. In this study, we identified a critical role for type I interferon (IFN) in epigenetic regulation during A. baumanniiinfection and established a central role for it in multiple cell death pathways. A. baumannii infection induced mixed celldeath constituted of apoptosis, pyroptosis, and necroptosis. Mechanically, A. baumannii triggered TRIF-dependent type IIFN production, which in turn induced the expression of genes Zbp1, Mlkl, caspase-11, and Gsdmd via KAT2B-mediatedand P300-mediated H3K27ac modification, leading to NLRP3 inflammasome activation, and potentially contributed toGSDMD-mediated pyroptosis and MLKL-dependent necroptosis. Our study offers novel insights into the mechanisms oftype I IFN and provides potential therapeutic targets for infectious and inflammatory diseases.