Poly (ADP-ribose) polymerase (PARP) inhibitors are effective in cells with homologous recombination (HR) deficiency, including BRCA1/2 mutation. However, PARP inhibitors remain a therapeutic challenge in breast and ovarian cancer due to inevitably acquired resistance in most cases. Therefore, strategies to overcome PARP inhibitor resistance are unmet clinical need. SRY-box transcription factor 5 (SOX5) plays a crucial role in development of various cancers but the role of SOX5 in PARP inhibitor resistance is poorly understood. This study identified SOX5 as a potential biomarker associated with PARP inhibitor resistance and addressed potential treatment strategies to overcome PARP inhibitor resistance using the olaparib-resistant preclinical model. We observed that SOX5 was significantly upregulated in olaparib-resistant cells and contributed to PARP inhibitor resistance by upregulating DNA repair pathway genes. Ectopic SOX5 overexpression contributed to PARP inhibitor resistance by suppressing DNA double-strand breaks (DSBs) in BRCA-mutated breast and ovarian cancer. SOX5 small interfering RNA combined with olaparib sensitized olaparib-resistant cells and suppressed the growth of olaparib-resistant xenografts in mice via increased DSBs represented by ɣH2AX formation. Mechanistically, SOX5 directly interacted with yes-associated protein 1 (YAP1) and promoted its nuclear translocation by suppressing the Hippo pathway. YAP1, in association with TEA domain family members (TEAD), upregulated HR-related gene expression and conferred PARP inhibitor resistance. Furthermore, the clinical relevance of SOX5 as a therapeutic target was supported by a significant association between SOX5 overexpression and poor prognosis in ovarian cancer on public mRNA microarray data sets. Therefore, we propose SOX5 as a promising therapeutic target for overcoming PARP inhibitor resistance in BRCA1/2-mutated breast and ovarian cancer.