The flavor enhancer monosodium glutamate (MSG), which is produced from glutamic acid, is frequently used as a food enhancer in processed foods. The usage of MSG as a food additive is still debated. Moreover, curcumin, the main active compound of turmeric extract, has antioxidant, anti-mutagenic, and antimicrobial properties; additionally, it has several pharmacological activities against many chronic diseases, and its conjugation with nanomaterials increases its efficacy. This work studied the protective and therapeutic impacts of curcumin nanoparticles (CUR-NPS) on cardiotoxicity persuaded by MSG. In this work, 40 adult male albino rats were used and divided into five groups (8 rats per group): control, CUR-NPS, MSG, therapeutic, and protective groups. At the end of the treatment period, the rats were sacrificed, and then the biochemical, molecular, and histopathological investigations were performed. The outcomes demonstrated that the curcumin nanoparticles reduced the levels of malondialdehyde (MDA), lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), endothelin-1 (End-1), heart fatty acid binding proteins (HFABP), calcium (Ca⁺²), and DNA damage while elevating the levels of both nitric oxide (NO) and total antioxidant capacity (TAC). Moreover, CUR-NPS improved the histopathological changes in heart tissue.