Abstract In an organism, cisplatin and its derivatives are known to interact with proteins besides their principal DNA target. These off-target interactions have major therapeutic consequences including undesired side effects, loss of bioavailability and emergence of resistance. Insulin is one of the prototypical protein targets of platinum drugs as it has been seen to be involved in bioavailability reduction and might also determine resistance in certain cancer lines. However, despite the interest in understanding the nature of the oxaliplatin–insulin adducts, no 3D models have been achieved so far. In this study, we apply our recent computational multiscale protocol optimized for bioinorganic interactions to provide structural insights into these systems. To do so, the initial structures are predicted by blind protein–metalloligand docking calculations optimized to account for a metal-containing species, and then refined using a Molecular Dynamics (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM) integrated protocol. The results are consistent with experimental information obtained from fragment analysis, and also provide novel structural information like conformational changes occurring upon binding and potential effects on the biological functions of the protein. This study opens an avenue towards applying similar strategies to a wide ensemble of metallodrug–protein/peptide systems for which no structural data are available.