Interferons (IFNs) and proinflammatory cytokines play an important role in the innate immune response to respiratory viruses, including coronaviruses (SARS-CoV). Metabolic profiling in the serum samples of coronavirus disease-19 (COVID-19) patients revealed altered cholesterol and tryptophan metabolism. Indoleamine-3,5-dioxygenase (IDO1) is the key enzyme involved in the tryptophan catabolism and induced by interferons and inflammatory cytokines. The regulation of IDO1 in immune cells and cancer was extensively studied. In this study, IDO1 regulation in human lung epithelial cells by coronaviruses and respiratory viruses as well as inflammatory cytokines was investigated. SARS-CoV-2 was a potent inducer of IFN–regulated metabolic enzymes such as IDO1, Cholesterol-25-hydroxylase (CH25H), Spermidine acetyltransferase (SAT1), and Sterile alpha motif and histidine/aspartic acid domain-containing protein (SAMHD1) at RNA levels in Calu-3 cells. Reconstitution of A549 lung epithelial cells with Angiotensin-converting enzyme 2 (ACE2) was necessary and sufficient to induce IDO1 at RNA levels. Influenza A virus (IAV) suppressed IDO1 RNA levels in a non-structural protein (NS1)-dependent manner in NHBE cells. In contrast, IDO1 RNA levels were dramatically induced in the lungs of mice infected with a reconstructed 1918 H1N1 influenza virus. Treatment of A549 cells with either type I or type II interferon induced IDO1 RNA levels. Furthermore, IDO1 levels were significantly higher in the lung tissues of COVID-19 patients in comparison with healthy controls. A mix of proinflammatory cytokines dramatically induced IDO1 and chemokine RNA levels in lung epithelial cells in a cell culture model, simulating the gene expression pattern in the lung tissue samples of COVID-19 patients. Furthermore, hypertonic saline solution (HTS) dramatically abrogated the gene expression induced by cytokine mix in human lung cells. The IDO1 protein interaction network included transcription factors STAT1 and STAT3. These studies suggest that IDO1 inhibition may be a potential therapeutic target in the treatment of viral and inflammatory diseases.