Hepatitis E virus (HEV) remains an important but largely understudied zoonotic pathogen. A universally available vaccine is lacking, and current treatments are limited by severe side effects, teratogenicity, and frequent therapeutic failures. Drug repurposing may therefore accelerate the discovery of effective anti-HEV therapies. We screened a library of 496 nucleoside and nucleotide analogs and derivatives to identify potential antiviral candidates. Ten compounds inhibited HEV replication by more than 60% while maintaining cell viability above 75%, including four that showed clear dose–response relationships. Among these, 4′-fluorouridine (4′-FIU) exhibited potent antiviral activity in both replication (EC50 ~ 5 µM) and infection (EC50 ~ 10 µM) assays against HEV-Kernow-C1/p6 and HEV-1 Sar55 strains. Its efficacy was further confirmed in extrahepatic cell lines (placental JEG-3, intestinal Caco-2, and renal HEK293T) as well as in primary human hepatocytes. Combination treatment with ribavirin produced an additive antiviral effect, while exogenous uridine reversed the inhibitory activity of 4′-FIU on HEV-3 replicon replication, indicating that the in vitro activity of 4′-FIU depends on depletion of intracellular UTP pools. To validate the in vivo efficacy of 4′-FIU, experiments in athymic nude rats as well as HEV-1 infection experiments in mice are currently ongoing. Altogether, these findings highlight 4′-FIU as a promising candidate for HEV therapy, addressing a critical unmet need in antiviral treatment.