The COVID-19 pandemic has prompted a rapid response in vaccine and drug development targeting SARS-CoV-2. Herein, we modelled a complete membrane-embedded SARS-CoV-2 spike (S) protein and used molecular dynamics (MD) simulations in the presence of benzene probes designed to enhance discovery of cryptic, potentially druggable pockets. This approach recapitulated lipid binding sites previously characterized by cryo-electron microscopy, and uncovered a novel cryptic pocket with promising druggable properties located underneath the 617-628 loop, which was shown to be involved in modulating the stability of cleaved S protein trimers a well as the formation of S protein multimers on the viral surface. A multi-conformational behaviour of this loop in simulations was validated using hydrogen-deuterium exchange mass spectrometry (HDX-MS) experiments, supportive of opening and closing dynamics. The pocket is the site of multiple mutations associated with increased transmissibility and severity of infection found in SARS-CoV-2 variants of concern including D614G. Collectively, this work highlights the utility of the benzene mapping approach in uncovering potential druggable sites on the surface of SARS-CoV-2 targets.