Cervical cancer (CC) is a common gynecological malignancy, and improving cisplatin sensitivity has become a hot topic in CC chemotherapy research. Polyphyllin I (PPI), a potent bioactive compound found in Rhizoma Paridis, known for its anticancer properties, remains underexplored in CC resistance. In this study, we evaluated PPI's impact on cisplatin-resistant CC cells and elucidated its underlying mechanism. Our findings reveal that PPI enhances the sensitivity of cisplatin-resistant CC cells to the drug, promotes apoptosis, and inhibits cell migration. Mechanistically, PPI was found to regulate p53 expression and its target genes, and suppressing p53 expression reverses PPI's sensitizing effect in drug-resistant CC cells. In conclusion, PPI showed promise in sensitizing cisplatin-resistant human CC cells to cisplatin treatment, suggesting that it could serve as a potent adjunct therapy for cervical cancer, particularly for cases that have developed resistance to cisplatin, thereby providing a promising basis for further clinical investigation into PPI for enhancing the efficacy of existing chemotherapy regimens in resistant cervical cancer.