Zika virus (ZIKV) infection is associated with serious, long-term neurological manifestations. There are currently no approved therapies for the treatment or prevention of ZIKV infection. Favipiravir (FAV) is a viral polymerase inhibitor with broad-spectrum activity. Our prior studies used static FAV concentrations and demonstrated promising activity. However, the anti-ZIKV activity of dynamic FAV concentrations has never been evaluated in a human cell line. Here we employed the hollow-fiber infection model (HFIM) to simulate the human pharmacokinetic (PK) profiles associated with the clinically utilized FAV dosage regimens against influenza and Ebola viruses and assessed the viral burden profiles. Clinically achievable FAV concentrations inhibited ZIKV replication in HUH-7 cells in a dose-dependent fashion (50% effective concentration = 236.5 μM). The viral burden profiles under dynamic FAV concentrations were predicted by use of a mechanism-based mathematical model (MBM) and subsequently successfully validated in the HFIM. This validated, translational MBM can now be used to predict the anti-ZIKV activity of other FAV dosage regimens in the presence of between-patient variability in pharmacokinetics. This approach can be extended to rationally optimize FAV combination dosage regimens which hold promise to treat ZIKV infections in nonpregnant patients.