Background: Resistance to existing therapies is currently the main reason for treatment failure in refractory/relapsed B-NHL patients, and therapy-induced senescence (TIS) is one of the important mechanisms of tumor drug resistance. Methods: Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector (Si-SENEX) and the empty vector negative (NC) to construct a stable transfection cell line with knockdown of SENEX. Effect of SENEX-silencing on B-NHL-TIS formation, cell function and cell cycle-related pathways was analyzed. We generated TIS model (using doxorubicin (dox)-inducible senescent B-NHL cells) combined with the specific CDK4/6 inhibitor Palbociclib (PAL) to observe that blocking CDK4/6 effects on TIS formation. In addition, expression levels of SENEX of 21 B-NHL patients and 8 healthy controls were tested by qRT-PCR, and the correlation between its expression and clinical indicators of patients was analyzed. Results: Downregulation of SENEX expression promotes G1-S phase transition and inhibits TIS formation in B-NHL cells to reduce the apoptosis resistance of B-NHL cells against chemotherapeutic drug DOX. Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence. Expression levels of SENEX in B-NHL patients were significantly increased compared to healthy controls, and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients. Conclusions: ARHGAP18/SENEX enhances apoptosis resistance of B-NHL via inhibiting CDK4/6 to prevent G1-S phase transition and promote TIS.