Deoxycytidine analogues (dC) are chemotherapy agents used to treat a range of solid and blood cancers. However, their clinical efficacy is often limited by resistance mechanisms. Cytidine deaminase (CDA) plays a key role of this resistance by deaminating dC analogues into inactive metabolites. Although pharmacological inhibitors targeting the CDA catalytic site have been developed, they exhibit limited efficacy and off-target effects. To overcome these limitations, alternative strategies to target CDA are needed. Here, we develop a CDA biodegrader using a cell-based screening approach. This biodegrader consists of an intracellular anti-CDA VHH fused to the SPOP E3 ubiquitin ligase. We demonstrate that the CDA biodegrader is highly specific and effectively depletes CDA across various pancreatic, lung, and acute myeloid leukaemia (AML) cancer cell lines. Furthermore, it sensitises these cells to dC analogue treatment in vitro. CDA-targeted degradation combined with gemcitabine leads to regression of pancreatic and lung tumours in vivo. These findings highlight CDA degradation as a promising therapeutic strategy to enhance the efficacy of dC analogues in cancer treatment.