BACKGROUND: Simvastatin (SMT) offers protection against diabetes mellitus related to coronary artery disease (DM-CAD) because of its cardioprotective, antioxidant, and anti-inflammatory effects. However, its low bioavailability and poor solubility limit its effectiveness. OBJECTIVE: This research aimed to develop and evaluate a nasal simvastatin-loaded novasomes (S-NOV) to enhance the drug's bioavailability, solubility, and effectiveness in treating DM-CAD. METHODS: The efficacy and bioavailability of the nasal S-NOV formulation were tested in a DM-CAD-induced rat model. RESULTS: The optimal S-NOV formulation demonstrated an 8.31-fold increase in bioavailability, a 4.64-fold enhancement in permeability, and a 4.71-fold increase in drug release. The nasal S-NOV formulation showed superior cardioprotective and antioxidant effects compared to oral SMT in various biomarkers, including lactate dehydrogenase, glutathione, and catalase. Histopathological and toxicology studies confirmed that the nasal S-NOV formulation was effective and safe. CONCLUSION: These findings suggest that nasal S-NOV formulation could be a viable and safe therapy for DM-CAD.