The outbreak of coronavirus disease 2019 (COVID-19) has caused a worldwide pandemic since 2019. A metabolic disorder is a contributing factor to deaths from COVID-19. However, the underlying mechanism of metabolic dysfunction in COVID-19 patients and the potential interventions are not elucidated. Here targeted plasma metabolomic is performed, and the metabolite profiles among healthy controls, and asymptomatic, moderate, and severe COVID-19 patients are compared. Among the altered metabolites, arachidonic acid and linolenic acid pathway metabolites are profoundly up-regulated in COVID-19 patients. Arginine biosynthesis, alanine, aspartate, and glutamate metabolism pathways are significantly disturbed in asymptomatic patients. In the comparison of metabolite variances among the groups, higher levels of l-citrulline and l-glutamine are found in asymptomatic carriers and moderate or severe patients at the remission stage. Furthermore, l-citrulline and l-glutamine combination therapy is demonstrated to effectively protect mice from coronavirus infection and endotoxin-induced sepsis, and is observed to efficiently prevent the occurrence of pulmonary fibrosis and central nervous system damage. Collectively, the data reveal the metabolite profile of asymptomatic COVID-19 patients and propose a potential strategy for COVID-19 treatment.