The cardiovascular benefits of eicosapentaenoic acid ethyl ester (EPA-E) in MACE reduction might extend beyond its triglyceride (TG)-lowering effects. However, the mechanism behind remains unknown. This study investigated whether EPA-E exerts cardioprotection in the setting of myocardial infarction (MI). Hypertriglyceridaemia (HTG) was induced in male rats by a high-sucrose diet (>175 mg·dL-1; baseline). Hypertriglyceridaemia rats were administered for 2 weeks high-dose EPA-E supplementation (HTG + EPA-E; n = 21) or placebo (HTG; n = 27) in combination with the diet. A control diet group (CD; n = 15) was included. After 2 weeks, MI was induced by transient coronary ligation and animals were sacrificed 24 h thereafter for infarct size, molecular, histological, and -omic analyses. Echocardiography was performed. HTG + EPA-E animals displayed lower circulating TG levels and better cardiac function as compared to HTG group. HTG + EPA-E animals showed smaller infarcts (P < 0.05 vs both groups), and MI-related mortality was 29% in EPA-E-treated animals (reaching levels comparable to those of the CD group), whereas it was 56% in HTG animals (P = 0.07). No correlation was observed between circulating TG levels and MI-related infarct size or mortality. Cardiac function was similarly deteriorated in all animals post-MI. Eicosapentaenoic acid ethyl ester treatment was associated with lower TG-related cardiolipotoxicity, apoptosis, fibrosis, oxidative stress, pro-inflammatory cell recruitment and less mitochondrial dysfunction in the infarcted heart. EPA-E treatment favoured a pro-resolving response and improved metabolomic and lipidomic profiles both systemically and in the infarcted heart. Eicosapentaenoic acid ethyl ester treatment exerts direct cardioprotective effects and ameliorates cardiac metabolic and lipidomic signatures after MI regardless of its circulating TG-lowering effects.