Brain pericyte cells are essential to vascular development, blood-brain barrier (BBB) stability, cerebral blood flow, cytokine expression, and angiogenesis. During inflammation, pericytes secrete proinflammatory cytokines, migrate, and contribute to BBB breakdown and infiltration of immune cells into the brain. Recent work has focused on pericytes as key targets to treat neuroinflammation. P38 mitogen-activated protein kinase (MAPK) is a critical mediator of proinflammatory signaling. G protein coupled receptors (GPCRs) mediate atypical, direct binding of transforming growth factor-β activated kinase 1 binding protein 1 (TAB1) to p38 to induce p38 autophosphorylation in endothelial cells. Its role in pericytes has not been investigated. Using chemical and cell-penetrating peptide inhibitors, our studies reveal that GPCRs activate atypical p38 signaling in human brain pericyte-like cells. We also show that pericyte migration and morphological change are induced by α-thrombin, PGE2, and PDGF-BB. We predict that GPCR-mediated atypical TAB1-p38α inflammatory signaling in brain pericytes is a critical driver of neuroinflammation.