In order to rationalize the available data related to the antichagasic activity of Pt/Pd complexes containing 5-nitrofurylthiosemicarbazones, in the present work we carried out a PCM/DFT comparative characterization of 16 Pt(II)/Pd(II) compounds of general formula [MCl(2)L] and the corresponding 5-nitrofurylthiosemicarbazone ligands (L) using multivariate techniques to sort and classify them and to search for patterns correlating the biological activity with calculated physicochemical descriptors. The data allow us to rationally propose that these compounds might act through dual or even multiple mechanisms of action, with preferred paths that depend on both the nature of metal and ligand. Moreover, these results suggest that the complexes in the set would not react in vivo with DNA, being biotransformed earlier, before gaining access to nuclear DNA in the cell. The binding mode and inhibitory potency of a selection of metal complexes and ligands with Trypanosoma cruzi cruzipain and trypanothione reductase enzymes is also modeled through molecular docking.