Brain inflammation has been implicated as a critical mechanism responsible for the progression of neurodegeneration and characterized by glial cell activation accompanied by production of inflammation-related cytokines and chemokines. D-pinitol is a naturally occurring compound with therapeutic properties and a member of the inositol family. D-pinitol is a (3-O-methyl-D-chiro-inositol), which is a cyclic polyol in general. It is a naturally occurring substance that was identified and extracted from a variety of plants. Growing evidences suggests that D-pinitol has anti-inflammatory effects. In the present study, we tested this possibility using a lipopolysaccharide (LPS)-induced neuroinflammation model both in vitro and in vivo. To assess anti-Neuroinflammatory and neuroprotective efficacy of D-pinitol in response to LPS-stimulated model of neuroinflammation. For in vitro studies, we used primary rat mixed neuronal/glial culture to assess D-pinitol effects on LPS-induced model of neuroinflammation in cell viability by MTT assay and ROS production by DCFH-DA assay. To evaluate in vivo effects, mice were intraperitoneally (i.p.) injected with D-pinitol followed by LPS, and expression of pro-inflammatory cytokines was assessed by enzyme-linked immunosorbent assay (ELISA). While, expression of iNOS (inducible nitric oxide synthase), NF-?B and selected neuronal markers were measured by real time PCR. Activation of microglia and astrocyte in the brain was examined by CD68 and GFAP immunostaining. Results showed that D-pinitol significantly enhanced cell viability in LPS activated primary mixed neuronal/glial cell culture and able to counteract intracellular ROS production. Administration of D-pinitol following LPS injection (i.p.) significantly reduced inflammatory responses, such as inflammatory cytokines (IL-6, TNF-a, and IL-1ß) in serum and significantly reduced neuroinflammatory effects by NF-?B and iNOS suppression in brain. Th reactive gliosis (microglial and astrocytic activation) was significantly reduced in IHC stained brain tissue. D-pinitol is a potent suppressor of neuroinflammation in an LPS-induced model, by inhibiting NF-?B activation and suppression of microglial activation. The anti-inflammatory capability of D-pinitol may provide a new therapeutic avenue to ameliorate the inflammation-associated neurodegenerative conditions.