Abstract The binding of the V V oxidation products of two vanadium(IV) compounds, VO(dmpp) 2 and VO(maltolato) 2 , which have shown promising anti‐diabetic properties, to human serum albumin (HSA) in aqueous aerobic solution has been studied by 1 H saturation transfer difference (STD) NMR spectroscopy and computational docking studies. Group epitope mapping and docking simulations indicate a preference of HSA binding to the 1:1 VO 2 (dmpp)(OH)(H 2 O) – and 1:2 VO 2 (maltol) 2 – vanadium(V) species. By using known HSA binders, competition NMR experiments revealed that both complexes preferentially bind to drug site I. Docking simulations carried out with HADDOCK together with restraints derived from the STD results led to three‐dimensional models that are in agreement with the NMR spectroscopic data, providing useful information on molecular interaction modes. These results indicate that the combination of STD NMR and data‐driven docking is a good tool for elucidating the interactions in protein–vanadium compounds and thus for clarifying the mechanism of drug delivery as vanadium compounds have shown potential therapeutic properties.