Metabolic syndrome (MetS) is a non-communicable disease characterised by a cluster of metabolic irregularities. Alarmingly, the prevalence of MetS in people living with Human Immunodeficiency Virus (HIV) and antiretroviral (ARV) usage is increasing rapidly. This study aimed to look at biochemical mechanisms and epigenetic modifications associated with HIV, ARVs, and MetS. More specifically, emphasis was placed on mitochondrial dysfunction, insulin resistance, inflammation, lipodystrophy, and dyslipidaemia. We found that mitochondrial dysfunction was the most common mechanism that induced metabolic complications. Our findings suggest that protease inhibitors (PIs) are more commonly implicated in MetS-related effects than other classes of ARVs. Furthermore, we highlight epigenetic studies linking HIV and ARV usage to MetS and stress the need for more studies, as the current literature remains limited despite the advancement in and popularity of epigenetics.