The work discovers the possibility of twelve newly synthesized coumarin-based amide derivatives (1–12) as VKORC1 inhibitors, a central enzyme implicated in blood coagulation. The central aim was to evaluate their drug-like features and binding affinity through computational means. Each molecule was synthesized by varying the benzoic acid moiety of the molecule through different chemical groups. Then, they were docked against VKORC1 (PDB ID: 6WV4) using Auto Dock Vina to assess their binding affinity with the active site of the enzyme. In addition to that, their pharmacokinetics such as absorption and metabolism were predicted using Swiss ADME. Compounds 2 and 3 exhibited good binding to VKORC1, better than that of warfarin, the reference anticoagulant. Compounds 2 and 3 had stable interaction with critical residues in the enzyme active site. SAR analysis indicated that electron-donating groups of small size at the meta-position enhanced binding, whereas bulky or ortho-positioned groups decreased it. All compounds passed simple drug-likeness requirements, and most exhibited good oral absorption. Compounds 6 and 12 demonstrated excellent solubility, clean metabolic profiles, and high predicted bioavailability. The results reveal that these new coumarin derivatives, particularly compounds 2, 3, 6, and 12, possess strong potential as next-generation VKORC1 inhibitors. They possess good binding affinity with favorable pharmacokinetic profile, and thus are exciting candidates for safer anticoagulant development.