Outbreaks of hand, foot and mouth disease (HFMD), which is caused by Enterovirus 71 (EV71), have erupted in recent years. Andrographolide sulfonate (Trade name: Xiyanping injection) has been recommended to treat severe HFMD in China because of its conventional antithermic and antitoxic activities, but its actual mechanism has not been revealed clearly until now. To explore its therapeutic efficacy and mechanism, a Xiyanping injection treatment mouse model was established. Based on the therapeutic model, routine clinical parameters and histopathologic changes were investigated, in the same time, viral loads, immune cells, inflammatory molecules and cell signaling pathways were determined. Xiyanping injection treatment protected mice from lethal EV71 challenge in a therapeutic regimen-dependent manner, which may mostly depend on its direct immunomodulatory activities on neutrophil and T lymphocyte. Reduced inflammatory molecular production of neutrophil and elevated T lymphocyte activity may result from its marked inhibition of some signaling pathways. Taken together, Xiyanping injection was an effective treatment for severe HFMD by improving hosts' immunity.