The anti-inflammatory function of Tanshionone IIA (TIIA), an active natural compound from Chinese herbal medicine Danshen, has been well-recognized and therefore TIIA was widely used to treat various inflammatory conditions associated with cardiac and lung diseases. Mucin 1 (Muc1) plays important anti-inflammatory roles in resolution of acute lung inflammation. In this study, we investigated the effects of TIIA on lipopolysaccharide (LPS)-induced acute lung inflammation, as well as its relationship to Muc1 expression in mouse lung and MUC1 in human alveolar epithelial cells. TIIA pretreatment significantly inhibited LPS-induced pulmonary inflammation in both Muc1 wild type (Muc1^+/+) and knockout (Muc1^-/-) mice, as manifested by reduced neutrophils infiltration, and reduced TNF-α and KC levels in bronchoalveolar lavage (BAL) fluid. The inhibitory effects of TIIA on airway inflammation were associated with reduced expression of Muc1 in Muc1^+/+ mouse lung. Moreover, pretreatment with TIIA significantly inhibited LPS-induced MUC1 expression and TNF-α release in A549 alveolar epithelial cells. TNF-α upregulated MUC1 mRNA and protein expression in A549 cells, which was inhibited by pretreatment with TIIA. The LPS induced-MUC1 expression was blocked when A549 cells were transfected with siRNA targeting for TNF-α receptor 1 (TNFR1). Further, TIIA inhibited LPS-induced nuclear translocation of NF-B and upregulation of TLR4 in A549 cells. Taken together, these results demonstrated that TIIA suppressed LPS-induced acute lung inflammation regardless the presence of Muc1, and TIIA inhibited LPS- and TNF-α-induced MUC1/Muc1 expression in airway epithelial cells, suggesting MUC1/Muc1 does not account for the mechanisms of the anti-inflammatory effects of TIIA in the airway.