HIV persists in central nervous system (CNS) reservoirs, where infected microglia and macrophages drive neuroinflammation, oxidative stress, and neuronal damage, contributing to HIV-associated neurocognitive disorder (HAND). Nanoparticle-based drug delivery systems, particularly poly(lactic-co-glycolic acid) (PLGA) nanoparticles, offer a promising strategy to improve CNS antiretroviral therapy (ART) delivery. This study aimed to evaluate the efficacy of co-administration of PLGA nanoparticles (NPs) encapsulating elvitegravir (EVG) and curcumin (CUR) in targeting CNS reservoirs, reducing neuroinflammation, and mitigating oxidative stress. PLGA NPs encapsulating EVG and CUR (PLGA-EVG and PLGA-CUR) were prepared via the nanoprecipitation method. The NPs were characterized for size, zeta potential, and encapsulation efficiency (EE). Their therapeutic efficacy was evaluated in vitro using U1 macrophages and in vivo in Balb/c mice. Key parameters, including cytokine levels, oxidative stress markers, and neuronal marker expression, were analyzed. The PLGA-EVG and PLGA-CUR NPs demonstrated high EE% (~90.63 ± 4.21 for EVG and 87.59 ± 3.42 for CUR) and sizes under 140 nm, ensuring blood-brain barrier (BBB) permeability. In vitro studies showed enhanced intracellular EVG concentrations and reductions in proinflammatory cytokines (IL-1β, TNFα, and IL-18) and improved antioxidant capacity in U1 macrophages. In vivo, the co-administration of NPs improved CNS drug delivery, reduced neuroinflammation and oxidative stress, and preserved neuronal markers (L1CAM, synaptophysin, NeuN, GFAP). PLGA-based co-delivery of EVG and CUR enhances ART CNS drug delivery, mitigating neuroinflammation and reducing oxidative stress. These findings highlight the potential of nanoparticle-based ART strategies to address limitations in current regimens and pave the way for more effective HAND therapies. Future studies should focus on optimizing formulations and evaluating safety in chronic HIV settings.