Human immunodeficiency virus 1 (HIV) infects myeloid cells in the central nervous system (CNS) and establishes a reservoir that persists despite antiretroviral therapy (ART). Infection leads to a 30-50% risk of developing HIV-associated neurocognitive disorders (HAND), a collection of mood, motor, and memory dysfunction that can manifest without gross neurodegeneration. Several causal mechanisms have been proposed, including activation of myeloid cells and glia, glutamate-mediated excitotoxicity, and direct neurotoxic effects of ART itself. In part one of this study, we used human induced pluripotent stem cell (iPSC)-derived (i3) neurons to identify the effects of these insults in a model of pure glutamatergic neurons. We found i3 neurons resisted death following exposure to HIV-infected myeloid cell supernatants and integrase inhibitors, contrasting reports in primary models. Further investigation determined i3 neurons were resistant to N-methyl-D-aspartate (NMDA) receptor-mediated toxicity. Using microelectrode arrays and RNA-seq, we recorded altered spontaneous neuronal activity and co-occurring changes in gene expression that both validated established pathways and identified novel targets for future studies of HIV neurotoxicity. In part two, we focused on combatting myeloid cell-mediated inflammation via cannabinoid receptor 2 (CB2), which negatively regulates cytokine release. Using monocyte-derived macrophages (MDMs) and iPSC-derived microglia (iMg), we found that CB2 activation dose-dependently impaired HIV replication in MDMs and iMg, although the effective doses and effect size varied. Similarly, while CB2 signaling globally reduced cytokine release from HIV-MDMs, this was not true in iMg. Transcriptomic analysis revealed the most differentially expressed pathways following cannabinoid treatment in MDMs involved interferon signaling and the integrated stress response, while in iMg, phagocytic pathways were altered alongside the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway. We determined that treating HIV-infected iMg with CB2-specific agonists suppressed activation, but not priming, of the NLRP3 inflammasome, reducing IL-1β release. This combined work identified phenotypes and pathways associated with NMDA-independent neuroinflammation, revealed cell-type differences in the HIV-infected myeloid cell cannabinoid response, and demonstrated that CB2 agonists can regulate the NLRP3 inflammasome in microglia, demonstrating potential as a therapeutic intervention in HAND.