Viral and bacterial severe pneumonia are leading causes of mortality across the globe. Evodiamine (Evo), a botanical alkaloid, has anti‑inflammatory and antibacterial properties. In the present study, the effect of Evo on severe pneumonia induced by methicillin‑susceptible Staphylococcus aureus (MSSA) following cytomegalovirus (CMV) reactivation, and its mechanism, were evaluated. In vitro, the protein and mRNA expression levels of inflammatory cytokines were determined by enzyme‑linked immunosorbent assay and reverse transcription‑quantitative polymerase chain reaction analysis, respectively. The expression levels of associated proteins of the nuclear factor (NF)‑κB and mitogen‑activated protein kinase (MAPK) signaling pathways were measured by western blot analysis. In vivo, mortality rate, weight loss, histological changes, lung bacteria count, inflammatory cytokines, and the expression proteins of associated with the NF‑κB and MAPK signaling pathways were examined. The results revealed that Evo dose‑dependently reduced the protein and mRNA expression levels of tumor necrosis factor (TNF)‑α, interleukin (IL)‑6 and IL‑1β, and inhibited the levels of phosphorylated (p‑) inhibitor of NF‑κBα, p‑extracellular signal‑regulated kinase, p‑c‑Jun N‑terminal kinase and p‑p38, and decreased the nuclear translocation of NF‑κB/p65 in BEAS‑2B cells infected with MSSA. Furthermore, Evo markedly improved survival rate, decreased body weight loss and bacterial count, and attenuated lung histological alterations and the levels of inflammatory factors. In addition, the NF‑κB and MAPK signaling pathways were significantly inhibited. Taken together, Evo effectively alleviated pneumonia via the NF‑κB and MAPK pathways and may be a potential therapeutic agent for treating severe pneumonia.