Metabolic syndrome (MetS) is a non-communicable disease characterized 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. Insulin resistance is a common characteristic of MetS that leads to the development of Type 2 diabetes mellitus (T2DM). The progression of insulin resistance is strongly linked to inflammasome activation. This study aimed to draw links between the combinational use of Tenofovir disoproxil fumarate (TDF), Lamivudine (3TC), and Dolutegravir (DTG), and inflammasome activation and subsequent promotion of insulin resistance following a 120 h treatment period in HepG2 liver in vitro cell model. Furthermore, we assess microRNA (miR-128a) expression as a negative regulator of the IRS1/AKT signaling pathway. The relative expression of phosphorylated IRS1 was determined by Western blot. Transcript levels of NLRP3, IL-1β, JNK, IRS1, AKT, PI3K, and miR-128a were assessed using quantitative PCR (qPCR). Caspase-1 activity was measured using luminometry. Following exposure to ARVs for 120 h, NLRP3 mRNA expression (p = 0.0500) and caspase-1 activity (p < 0.0001) significantly increased. This was followed by a significant elevation in IL-1β in mRNA expression (p = 0.0015). Additionally, JNK expression (p = 0.0093) was upregulated with coinciding increases in p-IRS1 protein expression (p < 0.0001) and decreased IRS1 mRNA expression (p = 0.0004). Consequently, decreased AKT (p = 0.0005) and PI3K expressions (p = 0.0007) were observed. Interestingly miR-128a expression was significantly upregulated. The results indicate that combinational use of ARVs upregulates inflammasome activation and promotes insulin resistance through dysregulation of the IRS1/PI3K/AKT insulin signaling pathway.