MUC1 is transmembrane mucin aberrantly overexpressed in various cancers. However, little is known about how MUC1 expression is associated with hypoxia, glucose metabolism, and epidermal growth factor receptor (EGFR) pathway, which are related to cancer progression. The aim of this study is to evaluate the relationship between MUC1 expression and these molecular markers in lung cancer. Of all 126 patients, high-grade polarized expression (HP), low-grade polarized expression (LP), and depolarized expression (DP) group were 50 (39.7%), 35 (27.8%), and 41 (32.5%), respectively. Depolarized MUC1 expression was significantly associated with poor outcome and was closely correlated with glucose metabolism (Glut1), hypoxia (HIF-1α), angiogenesis (vascular endothelial growth factor and microvessel density), amino acid metabolism (LAT1), and EGFR expression. High-grade polarized MUC1 expression was associated with favorable prognosis and adenocarcinoma. Depolarized MUC1 expression was significantly associated with poor outcome. Glucose metabolism, hypoxia, angiogenesis, amino acid metabolism, and EGFR pathway may play an important role in the development of depolarized MUC1 expression.