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Clinical treatment of cancer commonly incorporates X‐ray radiation therapy (XRT), and developing spatially precise radiation‐activatable drug delivery strategies may improve XRT efficacy while limiting off‐target toxicities associated with systemically administered drugs. Nevertheless, achieving this has been challenging thus far because strategies typically rely on radical species with short lifespans, and the inherent nature of hypoxic and acidic tumor microenvironments may encourage spatially heterogeneous effects. It is hypothesized that the challenge could be bypassed by using scintillating nanoparticles that emit light upon X‐ray absorption, locally forming therapeutic drug depots in tumor tissues. Thus a nanoparticle platform (Scintillating nanoparticleDrugDepot; SciDD) that enables the local release of cytotoxic payloads only after activation by XRT is developed, thereby limiting off‐target toxicity. As a proof‐of‐principle, SciDD is used to deliver a microtubule‐destabilizing payload MMAE (monomethyl auristatin E). With as little as a 2 Gy local irradiation to tumors, MMAE payloads are released effectively to kill tumor cells. XRT‐mediated drug release is demonstrated in multiple mouse cancer models and showed efficacy over XRT alone (p < 0.0001). This work shows that SciDD can act as a local drug depot with spatiotemporally controlled release of cancer therapeutics.