Neuro-inflammation is widely regarded as the inflammation occurred in the central nervous system (CNS) tissue, which authentically involved in the pathogenesis such as depression although the underlying mechanism remains to be elucidated. Malva sylvestris (MS), a plant widely used in traditional medicine to mitigate urological, respiratory and oral diseases, exhibits excellent anti-oxidative and anti-inflammatory properties. In the present study, we first used LPS-induced depression-like mice to evaluate the neuro-protective effect of MS extract. We found that, after 7 days' administration of MS extract, the cognitive impairment of LPS-induced depression-like mice was efficiently alleviated, evaluated by behavioral test including the Open field, Morris water maze (MWM), Elevated plus-maze (EPM) and Rota-rod test. Furthermore, we found that MS extract also inhibited the LPS-induced neuron apoptosis and astrogliosis both in the cortex and the CA1 region of hippocampus. Finally, our findings showed that the extract of MS relieved inflammatory stress induced by LPS injury, indicated by the down-regulation of IL-1β/6 and TNF-α, and up-regulation of IL-4 level both in vitro and in vivo. Collectively, MS extract exhibits neuro-protective activity in vivo, and therefore, it may be widely used for food to relieve the symptoms of neuro-inflammation associated disorders such as depression.