Understanding insect chemical sensing is key for new pest control strategies. While structural biology has advanced knowledge of insect odorant receptor (OR) detection of volatile compounds, ligand binding/dissociation thermodynamics and kinetics remain unclear. To address this, we used molecular dynamics simulations, enhanced sampling, and machine learning to study eugenol (EOL) and DEET binding/unbinding with MhOR5, an ancient insect OR. Unbiased MD revealed subtle EOL/DEET binding differences in the pocket. We identified W158 as a potential gating residue. Two ligand access pathways (aqueous phase, membrane interface) were uncovered, with the latter more favorable. Free energy (FEP) and kinetic (OPES-Flooding) calculations confirmed DEET binds MhOR5 more stably (-11.2 kcal/mol vs. EOL’s -8.4 kcal/mol) and associates ~3x faster, while EOL dissociates ~3 orders of magnitude faster. Notably, EOL’s stronger electrical response highlights complex ligand binding-signal transduction interplay. Collectively, our work gives atomistic insights into MhOR5 ligand recognition/binding/release, emphasizing key thermodynamic/kinetic factors. It suggests insect odorant responses stem from affinity differences and binding dynamics/kinetics, enhances OR function understanding, and provides a framework for studying other receptors.