Influenza A virus (H1N1), a swine-origin influenza A virus, causes seasonal epidemics that result in severe illnesses and deaths. Leonurine has been reported to function as an anti-inflammatory agent with protective effects on nervous, urinary and cardiovascular systems. However, the therapeutic effects of leonurine on the pneumonia caused by H1N1 infection remain unclear. Hematoxylin and eosin staining was performed to evaluate the lung injuries of mice infected by H1N1. The amount of immune cells was analyzed by flow cytometry. Enzyme-linked immunosorbent assay was used to evaluate the alteration of multiple cytokines in lung tissues. Real-time quantitative polymerase chain reaction assay was performed to investigate the ribonucleic acid (RNA) levels of certain genes. The protein levels in toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR4/NF-κB) signaling were estimated by western blot assay. Leonurine treatment significantly inhibited the mortality caused by H1N1 infection. Leonurine treatment (60 mg/kg) alleviated the lung injuries caused by virus infection. The inflammatory cell accumulation and cytokine expression were inhibited by the leonurine administration. Leonurine inhibited the mRNA expression of pro-inflammatory cytokines in the lung homogenates at day 5 postinfection. Leonurine regulated the TLR4/NF-κB signaling in the lung homogenates of H1N1-infected mice at day 5 postinfection. Leonurine protects against H1N1 infection-induced pneumonia in mice.