The aggressive endometrial cancer subtype known as uterine serous carcinoma (USC) has a dismal survival rate. In advanced/recurrent HER2/neu-positive USC, trastuzumab is a known target because approximately 30% of USC overexpress HER2/neu. Researchers tested the effectiveness of olaparib, an inhibitor of poly (ADP-ribose) polymerase (PARP), and neratinib, an inhibitor of pan-c-erb, both alone and in combination, against uterine serous carcinoma (USC) cell lines and xenografts. Using flow cytometry, the effects of olaparib, neratinib, and olaparib/neratinib on the viability of a panel of USC cell lines expressing high and low levels of HER2/neu were evaluated in vitro. Downstream signaling influenced by neratinib/olaparib exposure was investigated by immunoblotting, and homologous recombination deficiency (HRD) signatures were analyzed in accordance with the methods published by Alexandrov et al. (Nature;2020;578:94-101). In vivo comparison of single- and dual-agent inhibition was performed utilizing 2 HER2/neu-positive USC-xenografts. Inhibition of HER2/neu 3+ cell lines in vitro was more effective with neratinib compared to olaparib (ARK1: P=0.0047; ARK2: P=0.0428), but no difference was seen against HER2/neu 1+ malignancies (ARK4). In vitro, the combination of olaparib with neratinib was superior to either drug used alone in terms of tumor suppression. Neratinib treatment boosted PARP activity (ARK1: P<0.0001; ARK2: P<0.0001), while olaparib exposure caused USC cells to express more HER2/neu (P<0.0001). USC xenografts with amplified HER2/neu genes were temporarily stunted in growth in vivo when treated with single-agent neratinib (ARK1:P<0.05; ARK2: P<0.05). The combination of the 2 inhibitors, on the other hand, resulted in a greater and more sustained growth suppression in both USC xenografts (ARK1: P<0.05; ARK2: P<0.05). To effectively combat primary HER2/neu + USC, olaparib and neratinib can be used together. Patients at USC with HER2/neu+, homologous recombination-proficient, chemotherapy-resistant cancers may benefit from this combination.