<p>NeuroHIV has emerged as a significant unmet challenge, manifesting as impairments in learning, memory, sensorimotor, and language in people living with HIV (PLWH). Despite the widespread use of antiretroviral therapy, the incidence of NeuroHIV remains high among PLWH. Microglial cells, as the main targets and reservoirs for HIV-1 infection, play crucial roles in sustaining HIV-1 persistence and contributing to neuroinflammation and neuroHIV pathogenesis. This review summarizes recent molecular studies that elucidate the role of HIV-1-related factors—such as the viral proteins trans-activator of transcription (Tat), gp120, and Vpr, HIV-1 RNAs, and associated microRNA and long non-coding RNAs and extracellular vesicles—in microglial activation through mechanisms including cellular senescence, ferroptosis, defective mitophagy, NLR family pyrin domain containing 3 activation, and NF-κB pathway modulation. These processes collectively lead to neuroinflammation and the development of NeuroHIV. This review presents the current understanding of non-replicative mechanisms in NeuroHIV, outlining challenges, shortcomings, and the current treatment status. Further, it identifies potential therapeutic targets linked to microglial activation. The overall goal is to stimulate further research into novel strategies for mitigating the neuroinflammatory processes driving cognitive decline.</p><p></p>