Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread around the world and became a global pandemic in 2020. One promising drug target for SARS-CoV-2 is the transmembrane protease serine 2 (TMPRSS2). This study was designed to explore the expression status, prognostic significance and molecular functions of TMPRSS2 in lung cancer. TMPRSS2 expression was investigated using the TIMER, Oncomine, UALCAN, GEO, HPA and TCGA databases. The prognostic value of TMPRSS2 was examined using Cox regression and a nomogram. KEGG, GO and GSEA were performed to investigate the cellular function of TMPRSS2 in lung cancer. The relationship between TMPRSS2 and immune infiltration was determined using the TIMER and CIBERSORT algorithms. TMPRSS2 mRNA and protein expression was significantly reduced in lung cancer. Decreased TMPRSS2 expression and increased DNA methylation of TMPRSS2 were associated with various clinicopathological parameters in patients with lung cancer. Low TMPRSS2 mRNA expression also correlated with poor outcome in lung cancer patients. Moreover, a nomogram was constructed and exhibited good predictive power for the overall survival of lung cancer patients. KEGG and GO analyses and GSEA implied that multiple immune- and metabolism-related pathways were significantly linked with TMPRSS2 expression. Intriguingly, TMPRSS2 expression associated with immune cell infiltration in lung cancer. More importantly, TMPRSS2 expression was markedly decreased in SARS-CoV-infected cells. These findings indicate that TMPRSS2 may be a promising prognostic biomarker and therapeutic target for lung cancer through metabolic pathways and immune cell infiltration.