Introduction:Most critically ill COVID-19 patients have bronchitis, pneumonia, and acute respiratory distress syndrome (ARDS) due to excessive inflammatory conditions. Corticosteroids have largely been prescribed for the management of inflammation in these patients. However, long-term use of corticosteroids in patients with comorbidities such as metabolic, cardiovascular, and other inflammatory disorders is ideally not recommended due to safety issues. A potential and safer anti-inflammatory therapy is therefore the need of the hour.Withania somnifera(WS), a well-known herbal medicine used during the pandemic in India to prevent SARS-CoV2 infection, also possesses anti-inflammatory properties.Methods:In the present study, we, therefore, evaluated the effect of the aqueous extract of the roots ofW. somniferain the cell-based assays and in the experimental animal models of LPS-induced inflammation.Results:In the NCI-H460, A549 cells and human peripheral blood mononuclear cells (PBMCs) pre-treatment withW. somniferareduced the LPS-induced expression of the pro-inflammatory cytokines. In addition,W. somniferaextract also showed potent anti-inflammatory activity in the lung tissues of BALB/c mice challenged intranasally with LPS. We observed a marked reduction in the neutrophil counts in the broncho-alveolar lavage (BAL) fluid, inflammatory cytokines, and fibrosis in the mice lungs pre-treated withW. somnifera. Results obtained thus suggest the potential utility ofW. somniferaextract in reducing airway inflammation and recommend the clinical evaluation ofW. somniferaextract in COVID-19 patients with a high propensity for lung inflammation.