Neuroinflammation plays important roles in the pathogenesis and development of neurodegenerative disorders. Lipopolysaccharide (LPS) induces neuroinflammation and causes neurotoxicity, which results in cell damage or memory impairment in different cells and animals. In the present study, we investigated the neuroprotective effects of MG53, a member of the TRIM family proteins, against LPS-induced neuroinflammation and neurotoxicity in vitro and in vivo. MG53 significantly protected HT22 cells against LPS-induced cell apoptosis and cell cycle arrest by inhibiting TNF-α, IL-6 and IL-1β expression. In addition, MG53 ameliorated LPS-induced memory impairment and neuronal cell death in mice. Interestingly, MG53 significantly promoted newborn cell survival, improved neurogenesis, and mitigated neuroinflammation evidenced by lower production of IL-1β and IL-6, less activation of microglia in the hippocampus of LPS treated mice. Further studies demonstrated that MG53 significantly inhibited TLR4 expression and nuclear factor-κB (NF-κB) phosphorylation in LPS treated HT22 cells and mice. Taken together, our results suggested that MG53 attenuated LPS-induced neurotoxicity and neuroinflammation partly by inhibiting TLR4/NF-κB pathway in vitro and in vivo.