Introduction: Zika fever is a disease caused by Orthoflavivirus zikaense (Zika virus, ZIKV), mainly transmitted by mosquitoes of the Aedes genus. The symptoms are classified as dengue-like, however, more severe cases can present neurological disorders, such as Guillain-Barré syndrome and microcephaly in newborns of infected pregnant women. ZIKV belongs to the family Flaviviridae that is characterized by viruses with a positive sense single stranded RNA. However, no vaccines or antiviral drugs are currently available against ZIKV, making the search for compounds with antiviral activity essential. Objective: Evaluate the antiviral activity of a Schiff base derived from amantadine coordinated to cobalt(II) on ZIKV replication. Methods: Cell viability and antiviral assays were conducted to determine the 50% effective concentration (EC₅₀), 50% cytotoxic concentration (CC₅₀), and selectivity index (SI = CC₅₀/EC₅₀). Immunofluorescence assays were used to measure infection levels. Vero E6 cells were infected with the ZIKV_PE243 strain at a multiplicity of infection (MOI) of 0.01. Results: The cobalt–Schiff base complex (Co-atdSali) reduced ZIKV infection by more than 90%, while the starting Co(II) salt alone and the free Schiff base (atdSali) used in the synthesis of Co-atdSali reduced infection by 44% and 8%, respectively. The complex also showed strong inhibition of ZIKV replication in the dose–response assay, with a selectivity index (SI) of 14.7, compared with 3.9 for Co(II) salt and 1.6 for atdSali. Conclusion: The Co-atdSali complex exhibits enhanced antiviral activity compared to its free ligands, indicating the potential of metal coordination as a promising approach for developing new antiviral drug candidates against ZIKV.