Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are primarily effective against BRCA1/2-mutated ovarian and breast cancers, but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA Damage repair (DDR) and our previous studies demonstrating the ability of DNMT1 inhibitors (DNMTis) to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant ovarian and breast cancers to PARPi therapy, independent of BRCA status. Ovarian and breast cancer cell lines (BRCA- wildtype/-mutant) were treated with the PARPi talazoparib and the DNMTi guadecitabine. Effects on cell survival, reactive oxygen species (ROS) accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient ovarian or breast cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression and overall survival were analyzed. The combination of guadecitabine and talazoparib synergized to enhance PARPi efficacy, irrespective of BRCA mutation status. Co-administration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation and further sensitized, in a cAMP/PKA-dependent manner, ovarian and breast cancer cells to PARPi. In addition, DNMTi enhanced PARP 'trapping' by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple negative breast cancer models. The novel combination of the next generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wildtype- or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers.