Silicosis is an uncurable occupational disease induced by crystalline silica. Increased prevalence of silicosis has resulted in the increased need for development of treatment options. Although macrophages respond first to silica, epithelial cells are also involved in silicosis. However, changes in protein and metabolite levels have not been reported simultaneously. We used mass spectrometry to profile changes in metabolites, proteins, and phosphorylation in silica-exposed BEAS-2B epithelial cells. Silica exposure increased TCA cycle, alanine, aspartate and glutamate metabolism, and aerobic glycolysis activity. In addition, protein levels in the endoplasmic reticulum were significantly altered, and phosphorylation of MAPK signaling proteins was increased. The results of this study increased understanding the role of epithelial cells in silicosis.