A series of 10 hydrazones were synthesized by condensation of the selected hydrazine and the appropriate aldehyde. After the characterization and electrochemical analysis of each compound, amoebicidal activity was evaluated in vitro against the HM1:IMSS strain of Entamoeba histolytica. The results showed the influence of the nitrobenzene group and the hydrazone linkage over the amoebicidal activity. Compound 1 presents a promising amoebicidal activity with an IC50 = 0.98 mM, which represents a 7-fold increase in the potency of cell growth inhibition with respect to metronidazole (IC50 = 6.8 mM). Moreover, compounds 2 and 4 present an amoebicidal activity comparable to the reference compound. These results show that the electronic environment of hydrazone derivatives reflected in redox potential values of the hydrazone linkage and the nitro group plays a fundamental role in the amoebicidal activity. The molecular structure of compound 1 was reported.