Neurodegenerative diseases have become a huge challenge to public health, such as Alzheimer's and Parkinson's diseases. Microglia driving inflammation in the central nervous system (CNS) has been involved in the pathological process of these disorders and could be novel therapy target. However, traditional anti-inflammatory drugs are not effective in alleviating neuroinflammation. In this study, a potential neuroprotective effect of a peptide-templated gold nanocluster (Au25Sv9) was investigated. Firstly, effect of the nanocluster on cytotoxins' secretion of activated BV-2 microglia cells was assessed. Results indicated Au25Sv9 nanocluster effectively attenuated the cytotoxicity of stimulated microglia cells towards neuronal cells. And the underlying mechanism of action was illuminated preliminarily. The secretions of IL-6, TNF-α and NO in activated microglia cells were inhibited by the nanocluster in a dose-dependent manner via suppressing the activation of NF-κB and p38 pathways. Moreover, the ability of the nanocluster to protect neuronal cells to against microglial cytotoxins was also evaluated. Treating neuronal cells with the nanoclusters could protect them from cytotoxicity induced by supernatants of stimulated microglia cells through up-regulating of hemeoxygenase-1 (HOX-1). This study suggested the peptide-templated gold nanocluster is able to reduce microglia-mediated cytotoxicity to neuronal cells and possess direct neuroprotective properties simultaneously. We deduce the gold nanocluster would be an effective therapeutic approach to against neuroinflammation driving neurodegenerative diseases in the future.