Chronic neuroinflammation, associated with central nervous system (CNS) pathologies, involves persistent microglial activation. Misfolded proteins in Alzheimer’s disease and mechanical CNS lesions initiate prolonged immune responses, contributing to neuronal damage. Recent literature suggests the induction of controlled immune modulation to foster neuro-restoration. We propose the use of protein kinase C (PKC) activators to modulate CNS innate immune cells (i.e., microglia) for regenerative therapeutic approaches. Therefore, we examined the molecular and functional effect of PKC activators (Prostratin and Bryostatin) in immortalized BV-2 cells and primary murine microglia. Western Blot (WB) and immunocytochemistry (ICC) analyses revealed significant increases in NF-KB phosphorylation (pNF-KB), one of the pathways downstream to PKC, in Prostratin-treated BV-2 cells. ICC analysis confirmed Prostratin-induced nuclear translocation of pNF-KB in BV-2 and primary murine microglia. Morphological alterations were investigated by quantifying microglial cell area and phagocytic activity was measured to explore microglial functionality. PKC activation increased microglial cell area associated with enhanced phagocytic activity. Finally, gene-expression and flow cytometry analysis were used to investigate the polarization of BV-2 microglia cells upon PKC activation. The absence of pro-inflammatory marker expression, together with the reduction of CD40 expression in lipopolysaccharide-exposed BV-2 cells, suggests potential neuroregenerative phenotypes for PKC-activated microglia cells.Prostratin and Bryostatin’s impact on microglial signaling reveals intricate complexities, with NF-KB activation hinting at pro-inflammatory responses. However, unexpected CD40 downregulation and absence of cytokine overexpression suggest diverse, unresolved pathways. The use of PKC activators holds therapeutic promise, offering transformative potential for neuroregenerative medicine by targeting microglial responses.