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Infections caused by <i>Fasciola</i> species are widely distributed in cattle and sheep causing significant economic losses, and are emerging as human zoonosis with increasing reports of human cases, especially in children in endemic areas. The current treatment is chemotherapeutic, triclabendazole being the drug of preference since it is active against all parasite stages. Due to the emergence of resistance in several countries, the discovery of new chemical entities with fasciolicidal activity is urgently needed. In our continuous search for new fasciolicide compounds, we identified and characterized six quinoxaline 1,4-di-<i>N</i>-oxide derivatives from our in-house library. We selected them from a screening of novel inhibitors against <i>Fh</i>CL1 and <i>Fh</i>CL3 proteases, two essential enzymes secreted by juvenile and adult flukes. We report compounds <b>C7</b>, <b>C17</b>, <b>C18</b>, <b>C19</b>, <b>C23,</b> and <b>C24</b> with an IC₅₀ of less than 10 &#181;M in at least one cathepsin. We studied their binding kinetics in vitro and their enzyme-ligand interactions in silico by molecular docking and molecular dynamic (MD) simulations. These compounds readily kill newly excysted juveniles in vitro and have low cytotoxicity in a Hep-G2 cell line and bovine spermatozoa. Our findings are valuable for the development of new chemotherapeutic approaches against fascioliasis, and other pathologies involving cysteine proteases.