BackgroundCisplatin is commonly used to treat cervical cancer while drug resistance limits its effectiveness. There is an urgent need to identify strategies that increase cisplatin sensitivity and improve the outcomes of chemotherapy.ResultsWe performed whole exome sequencing (WES) of 156 cervical cancer tissues to assess genomic features related to platinum-based chemoresistance. By using WES, we identified a frequently mutated locusSETD8(7%), which was associated with drug sensitivity. Cell functional assays, in vivo xenografts tumor growth experiments, and survival analysis were used to investigate the functional significance and mechanism of chemosensitization afterSETD8downregulation. Knockdown ofSETD8increased the responsiveness of cervical cancer cells to cisplatin treatment. The mechanism is exerted by reduced binding of 53BP1 to DNA breaks and inhibition of the non-homologous end joining (NHEJ) repair pathway. In addition,SETD8expression was positively correlated with resistance to cisplatin and negatively associated with the prognosis of cervical cancer patients. Further, UNC0379 as a small molecule inhibitor ofSETD8was found to enhance cisplatin sensitivity both in vitro and in vivo.ConclusionsSETD8was a promising therapeutic target to ameliorate cisplatin resistance and improve the efficacy of chemotherapy.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13578-023-01054-y.