The first report of Zika virus (ZIKV) outbreak was from the Yap Island (Micronesia) in 2007 then spreading across the world, being responsible for neutrotropic Guillain-Barré syndrome, neonatal microencephaly, and death cases. Currently, there are no licensed vaccines or even specific approved drugs to treat ZIKV infections. Thus, developing novel antiviral agents is crucial. The replication of this flavivirus depends on NS2B-NS3 protease complex, which represents a promising target for searching new drug candidates. Herein, we describe the solid-phase synthesis of a new furin-based peptidomimetic (ArC=CCO-Arg-Leu-Lys-Arg-NH₂), biological screening and in silico studies, involving docking using ChemPLP algorithm, molecular dynamics (MD), and DFT/B3LYP calculations. Fluorometric assays revealed the selective inhibition of ZIKV NS2B-NS3 (IC₅₀: 31.5±1.9 µM), when compared to other serine and cysteine proteases. Moreover, docking analyses displayed that the best binding conformation (FitScore: 83.36) interacts with 12 amino acid residues, including Asn¹⁵² (hydrophobic) and Ser¹³⁵ (H-bond) from the catalytic triad. Regarding MD simulations, we verified that the ligand-target complex remains stable from 50 to 200 ns. After the clusters’ evaluation, the most stable complex conformation was retrieved (at ~150 ns) for determining the Gibbs free-energy value by DFT calculations. Finally, we verified that our inhibitor exhibits a ΔG value of -67.42 kcal/mol, suggesting it has an efficient binding mode at the catalytic site of ZIKV NS2B-NS3 protease.