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The COVID-19 pandemic, driven by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spurred an urgent need for effective therapeutic interventions. The spike glycoprotein of the SARS-CoV-2 is crucial for infiltrating host cells, rendering it a key candidate for drug development. By interacting with the human angiotensin-converting enzyme 2 (ACE2) receptor, the spike initiates the infection of SARS-CoV-2. Linoleate is known to bind the spike glycoprotein, subsequently reducing its interaction with ACE2. However, the detailed mechanisms underlying the protein-ligand interaction remain unclear. In this study, we characterized the pathways of ligand dissociation and the conformational changes associated with the spike glycoprotein by using ligand Gaussian accelerated molecular dynamics (LiGaMD). Our simulations resulted in eight complete ligand dissociation trajectories, unveiling two distinct ligand unbinding pathways. The preference between these two pathways depends on the gate distance between two α-helices in the receptor binding domain (RBD) and the position of the N-linked glycan at N343. Our study also highlights the essential contributions of K417, N121 glycan, and N165 glycan in ligand unbinding, which are equally crucial in enhancing spike-ACE2 binding. We suggest that the presence of the ligand influences the motions of these residues and glycans, consequently reducing accessibility for spike-ACE2 binding. These findings enhance our understanding of ligand dissociation from the spike glycoprotein and offer significant implications for drug design strategies in the battle against COVID-19. Author summary: Our work explores the intricate process of ligand dissociation from the spike glycoprotein of SARS-CoV-2, the virus responsible for the ongoing COVID-19 pandemic. The spike glycoprotein plays a crucial role in the virus's ability to infect human cells by interacting with the ACE2 receptor. Our study investigates the molecular interactions involving the spike glycoprotein and linoleate, a small molecule with the potential to hinder viral entry by blocking ACE2 interaction. Using advanced computational simulations, we uncover the dynamic mechanisms governing linoleate dissociation from the spike protein, unveiling two distinct unbinding pathways. Our findings illuminate the structural changes of the spike glycoprotein during the dissociation process. Notably, we highlight the crucial roles of a gate formed by two α-helices and an N-linked glycan at position N343, which control the dissociation process and determine the unbinding pathway. These insights have significant implications for the development of novel antiviral therapies and improved COVID-19 vaccines. By unraveling the molecular details of this interaction, our work contributes to the global efforts aimed at combatting the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]