In this work a computational study of the mechanism of inhibition of cruzain, rhodesain, and cathepsin L cysteine proteases by the dipeptidyl nitroalkene Cbz‐Phe‐Ala‐CH=CH‐NO2 has been carried out by means of molecular dynamics simulations with hybrid QM/MM potentials. The free‐energy surfaces confirmed that the inhibition takes place by the formation of a covalent bond between the protein and the β‐carbon atom of the inhibitor. According to the results, the tested inhibitor should be a much more efficient inhibitor of cruzain than of rhodesain, and little activity would be expected against cathepsin L, in total correspondence with the available experimental data. The origin of these differences may lie in the different stabilizing electrostatic interactions established between the inhibitor and the residues of the active site and S2 pocket of these enzymes. These results may be useful for the rational design of new dipeptidyl nitroalkenes with higher and more selective inhibitory activity against cysteine proteases. Taking control: A computational study of the mechanism of inhibition of three cysteine proteases by the dipeptidyl nitroalkene Cbz‐Phe‐Ala‐CH=CH‐NO2 shows that the inhibition takes place by the formation of a covalent bond between the protein and the Cβ of the inhibitor (see figure). The inhibitory activity of the dipeptidyl nitroalkene is dependent on the nature of the cysteine protease. The results may be useful for the rational design of more efficient and selective dipeptidyl nitroalkenes inhibitors against cysteine proteases.