HIV-1 infects monocytes derived macrophages (MDM), that migrate into the brain, and secrete neurotoxic molecules, including cathepsin B (CATB). Cocaine potentiates CATB secretion. Pretreatment with BD1047, a sigma-1 receptor antagonist, before cocaine exposure, reduces infection, CATB secretion, and neuronal apoptosis in vitro. We aim to elucidate intracellular pathways dysregulated after pretreatment with BD1047 versus those exposed to cocaine only, using Tandem Mass Tag Proteomics (TMT). Significant criteria of (|≥1.5| fold change, p-values ≤0.05) were used. Results demonstrate that pretreatment with BD1047 prior to cocaine shared six (6) proteins in comparison with the cocaine group that pertain to ubiquitination, ribosomal activity, and cell morphology. BD1047 uniquely dysregulated eighty (80) proteins when compared to infected cocaine group; and fifteen (15) of those were selected by Ingenuity Pathways analyses and literature review regarding infection, CATB and mitochondrial dysfunction. BD1047 pretreatment upregulated proteins related to oxidative phosphorylation activation (SLC25A-31), mitochondrial dysfunction (ATP5PD), ion transport dysfunction (VDAC2-3), endoplasmic reticulum transport hyperactivity (PHB, TMED10, CANX), and cytoskeleton remodeling (TUB1A-C, ANXA1). Similarly, downregulated proteins conveyed to Golgi transport (SURF4) and cell cytoskeleton proteins (PLEC, OLA1, GFAP). BD1047 uniquely dysregulates independent proteins from cocaine that might act as protective and balancing mechanisms for reducing mitochondrial damage, infection and CATB secretion.