Ononin, a natural isoflavone glycoside, has demonstrated antitumor activity in several malignancies, but its role in papillary thyroid carcinoma (PTC) remains unclear. Here, we show that ononin sensitizes PTC cells to cisplatin by attenuating the DNA damage response (DDR) through the E2F2/MDC1 axis. Ononin treatment suppresses cell proliferation, colony formation, and epithelial-mesenchymal transition in PTC cell lines. Pretreatment with ononin significantly reduces the half-maximal inhibitory concentration (IC₅₀) of cisplatin, indicating its potential as a chemosensitizing agent. Mechanistically, cisplatin resistance in PTC cells is associated with enhanced DDR and homologous recombination (HR) repair driven by E2F2. Ononin downregulates E2F2 expression, leading to reduced expression of MDC1, a key mediator of DDR and HR. Functional assays confirm that ononin-induced repression of E2F2 impairs DNA repair capacity and increases cisplatin sensitivity in cisplatin-resistant PTC cells. These findings identify ononin as a promising adjuvant candidate for overcoming cisplatin resistance in PTC by targeting the E2F2/MDC1-dependent DDR pathway.