Hippocampal pathology in diabetes is constantly investigated but the resultant health impact of the concomitant presence of alcohol and combined antiretroviral therapy (cART) in diabetes requires further studies to delineate toxicities inimical to hippocampal normal function. Forty-eight male Sprague Dawley rats were divided into eight groups (n = 6): negative control (NC), alcohol (AL), cART (AV), alcohol-cART (AA), diabetic control (DB), diabetes-alcohol (DAL), diabetes-cART (DAV), and diabetes-alcohol-cART (DAA) exposure groups. Following diabetes induction and sub-chronic (90 days) treatment exposure, hippocampal homogenates were profiled for pro-inflammatory cytokines and oxidative stress (MDA and GPx) using immunoassay, while apoptotic genes (BAX, Bcl2, and Caspase-3), insulin receptor genes (INSR and IRS-1), and blood-brain barrier (BBB) junctional proteins (claudin-5, and occludin) gene expression were assessed using qPCR. Histomorphology of hippocampal neuronal number, nuclei area, and volume of dentate gyrus and neurogenesis were accessed using Giemsa stain, Ki67, and DCX histochemistry respectively. A central hippocampal effect that underpins all treatments is the reduction of DG neuronal number and antioxidant (GPx), highlighting the venerability of the hippocampal dentate gyrus neurons to diabetes, alcohol, cART, and their combinatorial interactions. Additionally, elevated BAX, Bcl2, and IRS1 mRNA levels in the DAL group, and their downregulation in AA, suggests IRS-1-regulated apoptosis due to differential modulating effects of alcohol treatment in diabetes (DAL) in contrast to alcohol with cART (AA). Although the interaction in AA therapy ameliorated the independent alcohol and cART effects on MDA levels, pro-inflammatory cytokines, and DCX, the interaction in AA exacerbated a deficiency in the expression of INSR, IRS-1 (insulin sensitivity), and BBB mRNA which are implicated in the pathogenies of diabetes. Furthermore, the diabetic comorbidity groups (DAV, DAL, and DAA) all share a central effect of elevated hippocampal oxidative stress, BAX, and Caspase-3 mRNA expression with the reduced number of hippocampal neurons, dentate gyrus volume, and neurogenesis, highlighting neurodegenerative and cognitive deficiency implication of these comorbidity treatments. Considering these findings, assessment of hippocampal well-being in patients with these comorbidities/treatment combinations is invaluable and caution is advised particularly in alcohol use with cART prophylaxis in diabetes.