β-D-N⁴-Hydroxycytidine (NHC) derivatives with structural modifications at the C₄′, O₄′ or C₆ position and 4′-fluorouridine prodrugs were synthesized and evaluated for their antiviral activities against respiratory syncytial virus (RSV) or influenza virus (IFV) in vitro. The NHC derivatives were found inactive, but 4′-fluorouridine and its prodrugs had potent anti-RSV and anti-IFV activities. 4′-Fluorouridine was proved to be a nucleoside with poor stability, but the tri-ester prodrugs exhibited enhanced stability, especially tri-isobutyrate ester 1a. This prodrug also showed excellent oral pharmacokinetic properties in rats, with potential to be an oral antiviral candidate.