The experimental data collected over the past 15 years on the interaction of decavanadate(V) (V10O286-; V-10), a polyoxometalate (POM) with promising anticancer and antibacterial action, with G-actin, were rationalized by using several computational approaches (docking, density functional theory (DFT), and molecular dynamics (MD)). Moreover, a comparison with the isostructural and more stable decaniobate(V) (Nb10O286-; Nb-10) was carried out. Four binding sites were identified, named alpha, beta, gamma, and delta, the site alpha being the catalytic nucleotide site located in the cleft of the enzyme at the interface of the subdomains II and IV. It was observed that the site alpha is preferred by V-10, whereas Nb-10 is more stable at the site beta; this indicates that, differently from other proteins, G-actin could contemporaneously bind the two POMs, whose action would be synergistic. Both decavanadate and decaniobate induce conformational rearrangements in G-actin, larger for V-10 than Nb-10. Moreover, the binding mode of oxidovanadium(IV) ion, V(IV)O2(+), formed upon the reduction of decavanadate(V) by the -SH groups of accessible cysteine residues, is also found in the catalytic site a with (His 161, Asp 154) coordination; this adduct overlaps significantly with the region where ATP is bound, accounting for the competition between V-10 and its reduction product (VO2+)-O-IV with ATP, as previously observed by EPR spectroscopy. Finally, the competition with ATP was rationalized: since decavanadate prefers the nucleotide site alpha, Ca2+-ATP displaces V-10 from this site, while the competition is less important for Nb-10 because this POM shows a higher affinity for beta than for site a. A relevant consequence of this paper is that other metallodrug-protein systems, in the absence or presence of eventual inhibitors and/or competition with molecules of the organism, could be studied with the same approach, suggesting important elements for an explanation of the biological data and a rational drug design.