The use of nanotechnology is becoming increasingly significant as a tool that can provide a range of options for the identification, inactivation, and therapy of coronavirus disease 2019 (COVID-19). The potential of nanoparticles as an alternative therapeutic agent to inactivate SARS-CoV-2 is continually being investigated. Herein, we have explored the interaction of 2D molybdenum disulfide (MoS2) nanosheets with the SARS-CoV-2 spike protein, human ACE2 receptor and the complex formed between them through molecular docking and atomistic simulations. The results indicated that MoS2 nanosheets can effectively bind to the receptor binding domain (RBD) of the spike protein with good docking energies. It is interesting to note that this also applied to the extensively glycosylated spike protein and its variations, Kappa and Delta. A significant loss of secondary structures was observed when MoS2 nanosheets interacted with the RBD of the spike protein. The nanosheets interacted strongly with the proteins through a number of hydrogen bonds and van der Waals interactions. Moreover, the binding of the MoS2 nanosheets at different locations of the RBD or ACE2 in the spike-RBD/ACE2 complex resulted in significant conformational changes. Detailed energetics and solvent accessibility calculations revealed that, when present at the interface, MoS2 nanosheets can be a potential inhibitory agent. The findings were supported by de-wetting calculations, indicating strong adherence of the RBD of spike protein on the MoS2 nanosheet and de-stability of the spike-ACE2 interaction. Thus, the findings clearly demonstrate the antiviral potential of 2D MoS2 nanosheets, prompting its further exploration for combating COVID-19.