Understanding the unbinding kinetics of protein-ligand complexes is considered a significant approach for the design of ligands with desired specificity and safety. In recent years, enhanced sampling methods have emerged as effective tools for studying the unbinding kinetics of protein-ligand complexes at the atomistic level. MetAP-II is a target for the treatment of cancer for which not a single effective drug is available yet. The identification of the dissociation rate of ligands from the complexes often serves as a better predictor for in vivo efficacy than the ligands' binding affinity. Here, funnel-based restraint well-tempered metadynamics simulations were applied to predict the residence time of two ligands bound to MetAP-II, along with the ligand association and dissociation mechanism involving the identification of the binding hotspot during ligand egress. The ligand-egressing route revealed by metadynamics simulations also correlated with the identified pathways from the CAVER analysis and by the enhanced sampling simulation using PLUMED. Ligand 1 formed a strong H-bond interaction with GLU364 estimating a higher residence time of 28.22 ± 5.29 ns in contrast to ligand 2 with a residence time of 19.05 ± 3.58 ns, which easily dissociated from the binding pocket of MetAP-II. The results obtained from the simulations were consistent to reveal ligand 1 being superior to ligand 2; however, the experimental data related to residence time were close for both ligands, and no kinetic data were available for ligand 2. The current study could be considered the first attempt to apply an enhanced sampling method for the evaluation of the binding kinetics and thermodynamics of two different classes of ligands to a binuclear metalloprotein.