Objective To assess the effects of P21 inhibitor UC2288 on proliferation and apoptosis of nasopharyngeal carcinoma radioresistant cell line CNE-2R and the possible mechanisms. Methods The effect of UC2288 on cell viability was examined by a CCK-8 assay. The colony formation ability was investigated by a colony formation assay. Changes of cell morphology were observed by microscopy and Hoechst 33342 staining. An annexin V-APC/ 7-AAD assay was used to measure apoptosis. The protein levels of Bax, Cleaved-caspase 3, Caspase 3, Bcl-2, Survivin, γ-H2AX, P21, and PARP were measured by Western blot. Results The CCK-8 assay showed that UC2288 significantly reduced the viability and proliferation of CNE-2R cells in dose- and time-dependent manners. UC2288 also inhibited the colony formation of CNE-2R cells. Cells became round and atrophic, the nucleus shrunk, and the cell volume became smaller after treatment with UC2288. Annexin V-APC/ 7-AAD assays demonstrated that UC2288 induced apoptosis of CNE-2R cells in a dose-dependent manner. After treatment with UC2288, the expression levels of Bax, Cleaved-caspase 3, Caspase 3, and γ- H2AX increased accompanied by decreases of Bcl-2, Survivin, P21, and PARP. Conclusions UC2288 significantly inhibits the proliferation of CNE-2R cells, causes DNA damage, and induces apoptosis through possibly reducing the expression of PARP.