Alkhumra virus, a zoonotic pathogen in the Flaviviridae family, causes severe hemorrhagic fever in humans. Despite decoding its genetic sequence, vaccines and drugs remain unavailable. Given its crucial role in virion maturation, the NS2B/NS3 protease presents a promising therapeutic target. Here, we investigate the structural and dynamical changes induced by NS2B cofactor binding to NS3 protein through all-atom molecular dynamics simulations. The NS2B cofactor reduces the flexibility of NS3, particularly in regions in contact with NS2B, while the secondary structure remains unchanged. From an energetic perspective, the main driving forces in cofactor binding are nonbonding van der Waals and electrostatic interactions. We found that the protonation states of the catalytic triad residues significantly influence the geometry of the active pocket. Furthermore, a drug repurposing campaign utilizing ensemble docking and molecular dynamics simulations identified three compounds from the Drug- Bank database as potential NS2B/NS3 protease inhibitors. The catalytic serine residue with a deprotonated hydroxyl group exhibited the greatest contribution to the free energy of binding. This comprehensive analysis sheds light on the molecular interactions underlying ligand binding to NS2B/NS3, providing valuable insights for the development of effective inhibitors.