Head and Neck Squamous Cell Carcinoma (HNSCC) is one of the most common form of cancer worldwide. It has high incidence and mortality rate making it one of the top causes of cancer related deaths. Tremendous efforts have being made towards treatment of HNSCC but still the overall survival rate hasn’t improved much. Unregulated activation of Rho GTPase Ras-related C3 botulinum toxin substrate 1 or Rac1 has been reported in various tumor such as HNSCC, breast cancer, pancreatic cancer, etc. Rac1 is significant in activation and regulation of multiple signaling pathways and it’s aberrant activation leads to uncontrolled proliferation, invasion and metastasis which contributes to the hallmarks of cancer. Therefore for treating proliferative disorders such as cancer, inhibition of Rac1 could be a viable approach. Rho GTPases were earlier considered “undruggable” due to their picomolar binding affinity for their guanine nucleotides. In addition presence of high micromolar concentrations of GDP (> 30 μm) and GTP (> 300 μm) in the cell, led to unsuccessful attempts in identification of potent or selective nucleotide competitive GTPase inhibitors. Therefore we identified small molecule inhibitors that target the GEF binding site of the Rho GTPase instead of nucleotide binding site by performing high throughput screening, molecular dynamics simulations, free energy calculations and protein-ligand interaction studies. As a result of this study, we identified four potential inhibitors against RAC1. This study provides a significant in-depth understanding of the Rho GTPases and can prove beneficial in the development of potential therapeutics against HNSCC.