Coronary artery disease (CAD) is a leading cause of death worldwide. Despite effective anti-CAD drugs, the rising mortality suggests that more pharmacological targets need to be discovered to improve treatment effectiveness. This study explores and evaluates traditional medicinal plant (Piper betle (L.)) compounds against a new target identified through protein network analysis. Our network analysis suggests that the GRB2 protein could be a potential target that links most of the pathological pathway-related proteins in CAD. As a result, we evaluated potential compounds from Piper betle (L.) through ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling, docking, and molecular dynamics (MDs) simulation against the GRB2. The ADMET screening detected 49 druggable phytochemicals in Piper betle (L.). Further, screening through molecular docking showed that piperbetol has a higher predicted affinity towards the dimeric form of GRB2 (−8.10 kcal/mol) than other analyzed phytochemicals. Additionally, MD simulation demonstrated that piperbetol formed a stable complex with GRB2 during the simulation. In conclusion, piperbetol from Piper betle showed favorable binding with the identified CAD target. Further investigations are needed for pharmaceutical translation.