DNA methyltransferase inhibitors (DNMTis) are an epigenetic therapy for acute myeloid leukemia (AML) patients unfit for or unlikely to respond to intensive chemotherapy. DNMTis transcriptionally activate hypermethylated genes, and have been shown to activate endogenous retroviruses (ERVs) in a viral mimicry-inducing process that drives interferon (IFN) signaling. We previously reported that poly (ADP-ribose) polymerase inhibitors (PARPis) combine with DNMTis to induce an immune response that is mechanistically linked to reduction of DNA double-strand break repair activity in solid tumors. Here, we extend these mechanistic findings by showing that DNMTi+PARPi combination treatment induces a STING-dependent immune response to drive homologous recombination deficiency (HRD) in models of AML. Furthermore, we demonstrate for the first time that DNMTi-mediated ERV reactivation is significantly increased in TP53 mutant AML, and that such activation is the main driver of STING-dependent IFN signaling in this AML subtype. This is of particular importance given the poor prognosis associated with TP53 mutant AML and the potential relevance to other cancers with TP53 mutations. In contrast, AMLs with wild-type (WT) TP53 require both DNMTi+PARPis, rather than DNMTis alone, for activation of STING-dependent IFN/inflammatory signaling. Finally, we show that the induction of HRD by DNMTi+PARPi combination treatment is STING-dependent in both TP53 mutant and WT AMLs. These findings significantly increase our understanding of the mechanisms that underlie DNMTi+PARPi combination treatment efficacy, and suggest increased efficacy in patients with TP53 mutations.