OBJECTIVE: Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality around the world. Nuclear transcription factor kappa B (NF-κB) represents a factor that plays a major role in the pathogenesis of CVDs. The current study aims to investigate the modulatory effects of astaxanthin and its molecular mechanisms in rats with isoprenaline-induced myocardial infarction. MATERIALS AND METHODS: Rats were pretreated with astaxanthin daily for 14 days prior to inducing myocardial infarction with isoprenaline in the final two days. Blood and heart tissue samples were collected 24 hours after the last dose of isoprenaline was injected for biochemical and histological analysis. RESULTS: Isoprenaline-induced myocardial injury was demonstrated with histopathological examination of heart tissue and the significantly elevated serum troponin-I. Isoprenaline caused an increase in oxidative stress and a decrease in antioxidants. Toll-like receptor-4 (TLR4), NF-κB and tumor necrosis factor-α (TNF-α) expression levels were significantly higher in infarcted rats. Astaxanthin pretreatment had a significant preventive effect on all of the biochemical and molecular parameters tested in myocardial infarcted rats. CONCLUSIONS: Astaxanthin's cardioprotective effect has been linked to the inhibition of the TLR4/NF-κB signaling pathway. This inhibits the release of inflammatory cytokines, which can cause myocardial cell death. Because of its antioxidant and anti-inflammatory properties, astaxanthin is a promising cardioprotective agent.