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Metal‐based nanoparticles (NPs) have entered clinical use for enhancing radiotherapy, but the underlying mechanisms remain ambiguous. Herein, single‐cell analysis of two cell lines in response to megavolt irradiation and a radiomimetic drug, neocarzinostatin (NCS) after coculture with gold NPs with different surface coatings, polyethylene glycol (AuPEG), PEG, and transferrin (AuT) or silica (AuSiO2), is reported. Different surface chemistry presents a major challenge for objective comparison between the biological impacts where major differences in cell‐uptake exist. AuSiO2 NPs are the most efficient for promoting radiosensitization despite being associated with cells 10 times less than the actively targeted AuT NPs. Conversely, for cells exposed to NCS, AuSiO2 NPs impede the radiomimetic action and promote cell survival. AuT NPs enhance death of cells in combination with NCS showing that NPs can sensitize against cytotoxic agents in addition to radiation. While NPs contribute to radiosensitization (or enhancing/impeding chemotherapeutic drug activity), due to cell and cell line heterogeneity, the ultimate radiosensitivity of a cell appears to be dominated by its inherent radiosensitivity and how this cell‐regulated response is manipulated by NPs. This is evidenced through comparison of radiobiological response of cells with equivalent NP association rather than equivalent coculture conditions.