Metabolic syndrome (MetS) is a multifaceted entity with not all pathophysiological mechanisms fully elucidated. The definition for MetS requires at least three of the following criteria for diagnosis: increased waist circumference (cutoff varies by population); fasting blood glucose >100 mg/dL; serum triglycerides >150 mg/dL; serum HDL cholesterol <40 mg/dL in men and <50 mg/dL in women and systolic ≥130 mmHg or diastolic blood pressure ≥85 mmHg, respectively. The relationship between apolipoprotein E and metabolic syndrome is complex and multifaceted, involving interactions between genetics and environmental factors. Different ApoE isoforms influence lipid metabolism and the risk of developing MetS components in distinct ways. Understanding these interactions is essential for developing personalized prevention and treatment strategies to reduce cardiovascular risk and promote metabolic health. A holistic approach that includes personalized interventions based on the individual’s genetic profile, especially about ApoE isoforms, is crucial for the effective prevention and treatment of MetS.