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Platinum(IV) prodrugs of the [Pt(P_L)(A_L)(COXi)(OH)]²⁺ type scaffold (where P_L is 1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, A_L is 1<i>S</i>,2<i>S</i>-diaminocyclohexane, and COXi is a COX inhibitor, either indomethacin or aspirin) were synthesised and characterised, and their biological activity was explored. MTT assays showed that these complexes exhibit outstanding activity against a range of cancer cell lines, and nanomolar activities were observed. The most potent complex, <b>4</b>, exhibited a GI₅₀ of 3 nM in the Du145 prostate cancer cell line and was observed to display a 1614-fold increased activity against the HT29 colon cancer cell line relative to cisplatin. ICP-MS studies showed a linear correlation between increased cellular accumulation of the complexes and increased cytotoxicity, while an enzyme immunoassay showed that <b>1</b> and <b>2</b> inhibited COX-2 at 14 and 1.4 µM, respectively, which is comparable to the inhibition exhibited by indomethacin. These results suggest that while the cytotoxicity of prodrugs <b>1</b>–<b>4</b> was influenced by cellular uptake, it was not entirely dependent on either COX inhibition or lipophilicity.