Eicosanoids and their receptors act as key regulators of inflammation, calcium homeostasis, mitochondrial function, and cardiomyocyte survival, thereby contributing to the onset and progression of cardiac dysfunction. This review aims to summarize the evidence to underscore the pivotal role of eicosanoids and their receptors in the pathophysiology of cardiomyopathy, analysing the potential protective activity of traditional and natural compounds to counteract cardiovascular disease onset and progression. Among eicosanoid receptors, prostaglandin E2 receptor 3 (EP3), prostaglandin E2 receptor 4 (EP4), chemoattractant receptor expressed on type 2 helper T cells (CRTH2), and thromboxane prostanoid (TP) emerge as critical modulators with distinct and often opposing effects on cardiac physiology. While EP3 and CRTH2 are predominantly associated with detrimental outcomes such as impaired contractility and enhanced apoptosis, EP4 signalling consistently demonstrates cardioprotective properties, including improved calcium handling and preservation of mitochondrial integrity. These findings highlight the therapeutic potential of selectively targeting eicosanoid receptor pathways to mitigate cardiac remodelling and dysfunction. In parallel, increasing attention has been directed toward natural bioactive compounds as complementary strategies for cardioprotection. Polyphenols, flavonoids, carotenoids, and other nutraceuticals exert beneficial effects through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, often intersecting with eicosanoid signalling pathways. Their ability to modulate oxidative stress and inflammatory responses suggests a promising role in preventing or attenuating cardiomyopathy, particularly in metabolic and drug-induced contexts. Future research should focus on well-designed clinical trials, a deeper characterization of receptor-specific signalling networks, and the development of targeted therapies that combine pharmacological and nutraceutical approaches. Overall, a better understanding of eicosanoid-mediated mechanisms may open new ways for cardiomyopathy prevention and treatment, ultimately improving patient outcomes and reducing the burden of cardiovascular disease.