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Introduction: Programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors are standard-of-care treatment for metastatic NSCLC (mNSCLC). Intolerance to treatment/disease progression warrants additional lines of therapy. Real-world treatment patterns and efficacy outcomes after PD-1/PD-L1 use are insufficiently characterized to inform treatment decisions. Methods: Electronic health records of adults with stage IV NSCLC initiating PD-1/PD-L1 inhibitors as first-line monotherapy (cohort 1), first-line combination therapy (cohort 2), or second-line monotherapy (cohort 3) who received a subsequent line of therapy (i.e., index therapy) in the Flatiron NSCLC Core Registry Dataset were identified. Patient characteristics, types of index treatments/therapies, and associated index treatment outcomes were extracted. Results: A total of 1061 patients with mNSCLC were included in this analysis. In cohort 1 (n = 242), median real-world overall survival (mrwOS) with index therapies for the overall population was 9.18 months (95% confidence interval: 7.54–12.13); platinum-based chemotherapy was the most common index therapy (39.3%) with mrwOS of 12.52 months (8.39–not applicable). In cohort 2 (n = 145), mrwOS for the overall population was 6.43 months (5.34–7.61); vascular endothelial growth factor inhibitor plus chemotherapy was the most common index therapy (32.4%) with mrwOS of 5.97 months (4.95–7.34). In cohort 3 (n = 647), mrwOS for the overall population was 7.21 months (6.39–7.80); single-agent chemotherapy was the most common index therapy (45.4%) with mrwOS of 6.59 months (5.64–7.61). Conclusions: Real-world treatment patterns and survival outcomes of index therapies in mNSCLC after PD-1/PD-L1 use are variable. These analyses provide insights to optimize post–PD-1/PD-L1 treatments and inform standards of care.