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Parasitic diseases, including giardiasis caused by <i>Giardia lamblia</i> (<i>G. lamblia</i>), present a considerable global health burden. The limited effectiveness and adverse effects of current treatment options underscore the necessity for novel therapeutic compounds. In this study, we employed a rational design strategy to synthesize retroalbendazole (<b>RetroABZ</b>), aiming to address the limitations associated with albendazole, a commonly used drug for giardiasis treatment. <b>RetroABZ</b> exhibited enhanced in vitro activity against <i>G. lamblia</i> trophozoites, demonstrating nanomolar potency (IC₅₀ = 83 nM), outperforming albendazole (189 nM). Moreover, our in vivo murine model of giardiasis displayed a strong correlation, supporting the efficacy of <b>RetroABZ</b>, which exhibited an eleven-fold increase in potency compared to albendazole, with median effective dose (ED₅₀) values of 5 µg/kg and 55 µg/kg, respectively. A notable finding was <b>RetroABZ</b>’s significantly improved water solubility (245.74 µg/mL), representing a 23-fold increase compared to albendazole, thereby offering potential opportunities for developing derivatives that effectively target invasive parasites. The molecular docking study revealed that <b>RetroABZ</b> displays an interaction profile with tubulin similar to albendazole, forming hydrogen bonds with Glu198 and Cys236 of the β-tubulin. Additionally, molecular dynamics studies demonstrated that <b>RetroABZ</b> has a greater number of hydrophobic interactions with the binding site in the β-tubulin, due to the orientation of the propylthio substituent. Consequently, <b>RetroABZ</b> exhibited a higher affinity compared to albendazole. Overall, our findings underscore <b>RetroABZ</b>’s potential as a promising therapeutic candidate not only for giardiasis but also for other parasitic diseases.