Giardiasis remains a significant global health issue, and its treatment is increasingly hampered by the emergence of drug resistance and cross-resistance between nitroimidazoles and nitazoxanide. In this study, we evaluated the in vitro antigiardial activity, cytotoxicity, and potential mechanisms of action of seven structural analogs (CLB 1–7) derived from a hybrid structure combining nitazoxanide and clofibric acid. Among them, compounds CLB-3 and CLB-5 emerged as the most potent candidates, demonstrating exceptional efficacy against a nitazoxanide-resistant (NTZr) strain of Giardia lamblia, with potencies up to 43 and 60 times higher than that of the reference drug, respectively. Furthermore, both compounds demonstrated high selectivity for the parasite, exhibiting low cytotoxicity in human Caco-2 cells. To investigate the mechanism of action, functional biochemical assays revealed that treatment with these derivatives significantly reduced the intracellular ATP levels and altered the ADP/ATP ratio, indicating a direct impact on the parasite’s energy metabolism. These functional findings correlate closely with RT-qPCR transcriptional analyses and in silico molecular dynamics simulations; collectively, the data suggest a multi-target mechanism of action that may involve the disruption of energy homeostasis and the possible inhibition of key enzymes in the glycolytic pathway (PFOR, G6PD::6PGL, PK, and PPDK). In summary, these results identify compounds CLB-3 and CLB-5 as highly promising chemotherapeutic candidates for combating refractory giardiasis.