Platelet-derived growth factor-BB (PDGF-BB) has been reported to provide tropic support for neurons in the CNS. However, whether PDGF-BB regulates neurogenesis, especially in the context of HIV-associated neurological disorder and drug abuse, remains essentially unknown. In this study, we demonstrate that pretreatment of rat hippocampal neuronal progenitor cells (NPCs) with PDGF-BB restored proliferation that had been impaired by HIV Tat-cocaine via the cognate receptors. We identify the essential role of transient receptor potential canonical (TRPC) channels in PDGF-BB-mediated proliferation. Parallel but distinct ERK/CREB, phosphatidylinositol 3-kinase/Akt signaling pathways with downstream activation of mammalian target of rapamycin (mTOR)/eukaryotic translation initiation factor 4E-binding protein (4E-BP)-p70S6K and nuclear factor-κB were critical for proliferation. Blocking TRPC1 channel suppressed PDGF-mediated proliferation as well as PDGF-BB-induced ERK/CREB and mTOR/4E-BP-p70S6K activation, thereby underscoring its role in this process. In vivo relevance of these findings was further corroborated in Tat transgenic mice wherein hippocampal injection of recombinant AAV2-PDGF-B restored impaired NPC proliferation that was induced by Tat-cocaine. Together, these data underpin the role of TRPC1 channel as a novel target that regulates cell proliferation mediated by PDGF-BB with implications for therapeutic intervention for reversal of impaired neurogenesis inflicted by Tat and cocaine.