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Simple Summary: Although the initial clinical response of ovarian cancer patients to first-line platinum-based chemotherapy is often excellent, most patients relapse and develop resistance to treatment. However, the mechanism underlying resistance is unclear. DNA repair is the best-known effector of resistance to platinum-based agents, which damages DNA and activates DNA damage response. Two major DNA repair pathways exist, including homologous recombination (HR) and nonhomologous end joining (NHEJ). While the role of HR in platinum resistance is well studied, how NHEJ machinery affects platinum resistance in ovarian cancer remains largely unexplored. The goal of the current study is to decipher how NHEJ is involved in platinum resistance in ovarian cancer. Our study demonstrates XRCC4 in the NHEJ pathway specifically contributes to platinum resistance by mitigating the DNA damage caused by platinum drugs and provides preclinical evidence for targeting XRCC4 as a new strategy to battle cisplatin resistance in ovarian cancer treatment. DNA double-strand breaks (DSBs) caused by platinum drugs are dangerous lesions that kill cancer cells in chemotherapy. Repair of DSB by homologous recombination (HR) and nonhomologous end joining (NHEJ) is frequently associated with platinum resistance in ovarian cancer. While the role of the HR pathway and HR-targeting strategy in platinum resistance is well studied, dissecting and targeting NHEJ machinery to overcome platinum resistance in ovarian cancer remain largely unexplored. Here, through an NHEJ pathway-focused gene RNAi screen, we found that the knockdown of XRCC4 significantly sensitized cisplatin treatment in the platinum-resistant ovarian cancer cell lines. Moreover, upregulation of XRCC4 is observed in a panel of platinum-resistant cell lines relative to the parental cell lines, as well as in ovarian cancer patients with poor progression-free survival. Mechanistically, the increased sensitivity to cisplatin upon XRCC4 knockdown was caused by accumulated DNA damage. In cisplatin-resistant ovarian cancer, the JNK-cJUN complex, activated by cisplatin, translocated into the nucleus and promoted the transcription of XRCC4 to confer cisplatin resistance. Knockdown of XRCC4 or treatment of the JNK inhibitor led to the attenuation of cisplatin-resistant tumor growth in the xenograft mouse models. These data suggest targeting XRCC4 is a potential strategy for ovarian cisplatin resistance in ovarian cancer. [ABSTRACT FROM AUTHOR]