Background: In the past decade, therapies targeting EGFR, KRAS, ALK, ROS1, BRAF, NTRK, MET, RET variants, and PD-L1 expression were approved and recommended for use in advanced non-small cell lung cancer (aNSCLC). This study describes real-world patient characteristics, biomarker testing, treatment patterns, and clinical outcomes in patients with de novo stage IIIB–IV aNSCLC in the United States. Methods: This is a retrospective cohort study of patients with aNSCLC using TEMPUS oncology data. Patients were included if they were diagnosed with stage IIIB, IIIC, or IV NSCLC (index date) as their primary NSCLC diagnosis between 1/1/2012 and 12/31/2020, and were >18 years of age at index. Patients with an advanced diagnosis within 90-days of their primary diagnosis were defined as having de novo aNSCLC. Patient demographics and clinical characteristics including biomarker testing for EGFR, KRAS, ALK, ROS1, BRAF, NTRK, MET, RET alterations, and/or PD-L1 expression, as well as treatment patterns, were described. Median progression-free survival (PFS) and median overall survival (OS) were stratified by stage at diagnosis (IIIB/IIIC vs IV) and evaluated by Kaplan–Meier analysis. Results: A total of 7,624 patients met the study criteria. 12.5% (n = 955) were diagnosed at stage IIIB/IIIC versus 87.5% (n = 6,669) diagnosed at stage IV. Of the de novo patients with aNSCLC, 47.6% (n = 3,632) were female, median age (IQR) was 65.3 years (58.1–72.4), 67.4% (n = 5,136) were White, and 62.7% (n = 4,781) had evidence of biomarker testing. Biomarker testing was significantly more common among patients diagnosed at stage IV (64.9%, n = 4,325) than stage IIIB/IIIC (47.7%, n = 456; p < 0.001). At index, 10.3% (n = 785) of patients had evidence of brain metastasis, 49.2% (n = 3,749) were current or former smokers, and 66.7% (n = 5,086) had non-squamous histology. 69.1% (n = 5,269) received first-line treatment with chemotherapy (58.5%, n = 3,083), chemotherapy + immune checkpoint inhibitor (ICI) (20.8%, n = 1,096), ICI monotherapy (9.5%, n = 503), tyrosine kinase inhibitors (10.4%, n = 548), or other treatments (0.7%, n = 39). Among patients with de novo aNSCLC overall at stage IIIB/IIIC and stage IV, median PFS was 5.0 months (mos) (95% CI: 4.8, 5.3), 7.2 mos (95% CI: 6.3, 8.1), and 4.8 mos (95% CI: 4.6, 4.9; p < 0.0001), respectively; median OS was 13.9 mos (95% CI: 13.3, 14.5), 19.4 mos (95% CI: 16.8, 22.0), and 13.2 mos (95% CI: 12.6, 13.8; p < 0.0001), respectively. Conclusions: Among patients with de novo aNSCLC, those diagnosed at stage IIIB/IIIC had significantly longer median PFS and OS than those diagnosed at stage IV. Many real-world patients with aNSCLC were not tested for biomarkers for which there are now approved targeted therapies. Earlier diagnosis and increased biomarker testing may improve clinical outcomes in real-world patients with aNSCLC.