Lung carcinoma is the leading cause of death by cancer in the world. Nowadays, most patients will experience disease progression during or after first-line chemotherapy demonstrating the need for new, effective second-line treatments. The only approved second-line therapies for patients without targetable oncogenic drivers are docetaxel, gemcitabine, pemetrexed, and erlotinib and for patients with target-specific oncogenes afatinib, osimertinib, crizotinib, alectinib, and ceritinib. In recent years, evidence on the role of antiangiogenic agents have been established as important and effective therapeutic targets in non-small cell lung cancer (NSCLC). Nintedanib is a tyrosine kinase inhibitor targeting three angiogenesis-related transmembrane receptors (vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor). Several preclinical and clinical studies have proven the usefulness of nintedanib as an anticancer agent for NSCLC. The most important study was the phase III LUME-Lung 1 trial, which investigated the combination of nintedanib with docetaxel for second-line treatment in advanced NSCLC patients. The significant improvement in overall survival and the manageable safety profile led to the approval of this new treatment in Europe. This review focuses on the preclinical and clinical studies with nintedanib in NSCLC.