In human cells ClpP and ClpX are imported into the mitochondrial matrix, where they interact to form the ATP-dependent protease ClpXP and play a role in the mitochondrial unfolded protein response. We find that reducing the levels of mitochondrial ClpP or ClpX renders human cancer cells more sensitive to cisplatin, a widely used anti-cancer drug. Conversely, overexpression of HClpP desensitizes cells to cisplatin. Overexpression of inactive HClpP–S97A had no effect. Cisplatin resistance correlated with decreased cellular accumulation of cisplatin and decreased levels of diguanosine–cisplatin adducts in both mitochondrial and genomic DNA. In contrast, higher levels of cisplatin–DNA adducts were found in cells in which HClpP had been depleted. Changes in the levels of ClpP had no effect on the levels of CTR1, a copper transporter that contributes to cisplatin uptake. However, the levels of ATP7A and ATP7B, copper efflux pumps that help eliminate cisplatin from cells, were increased when HClpP was overexpressed. HClpP levels were elevated in cervical carcinoma cells (KB‐CP₂₀) and hepatoma cells (BEL-7404-CP₂₀) independently selected for cisplatin resistance. The data indicate that robust HClpXP activity positively affects the ability of cells to efflux cisplatin and suggest that targeting HClpP or HClpX would offer a novel mechanism for sensitizing cancer cells to cisplatin.