Background: Oxidative stress, inflammation, and endothelial dysfunction are important processes in the progression of atherosclerosis and the occurrence of acute coronary syndromes (ACSs). Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs) are present in marine organisms and have the capacity to reduce all these processes and, at the same time, the progression of atherosclerosis and the emergence of ACSs. Aim: To evaluate the role of Omega-3 PUFAs therapy on parameters of oxidative stress, inflammatory syndrome, endothelial dysfunction, and long-term prognosis in acute coronary syndromes. Methods: One thousand one hundred forty patients were admitted to Clinic County Emergency Hospital Brasov with ACS and were enrolled in a prospective study. The study was divided into four groups related to the type of ACS and treatment with Omega-3 PUFAs added to the optimal medical therapy (OMT). The effect of Omega-3 PUFAs therapy associated with the OMT was determined by measuring the dynamics of the following parameters: (a) oxidative stress—total antioxidant status (TAS), oxidated low density lipoprotein cholesterol antibodies (Ab anti-ox-LDL), IgG anti-Myeloperoxidase antibodies (IgG type Ab anti-MPO); (b) inflammatory syndrome—C-reactive protein and fibrinogen; (c) endothelial dysfunction—flow mediated dilation (FMD) and von Willebrand factor (vWf) activity, from baseline to 6 months of follow-up. Clinical events followed at 5 years were cardiovascular and sudden death, Non-ST and ST segment elevation ACS, in stent thrombosis and restenosis, stroke, readmission in hospital for ACS and for heart failure. Results: In ACS groups, treatment with Omega-3 PUFAs added to the OMT significantly decreased the parameters of oxidative stress, inflammatory syndrome, and endothelial dysfunction at 6 months of follow-up. Regarding the clinical events, a significant reduction in the risk of cardiovascular and sudden death and a decreased incidence of Non-ST and ST segment elevation ACS, in-stent restenosis, readmission for ACS and heart failure, was observed in Omega-3 PUFA-treated groups in comparison to control groups. Conclusions: In acute coronary syndromes, therapy with Omega-3 PUFAs added to the OMT resulted in a significant decrease of parameters of oxidative stress, inflammation, and endothelial dysfunction at 6 months and also a significant improvement in the long-term prognosis.