Background and Objectives: Clinically meaningful drug–drug interactions may be overlooked in oncology. Proton pump inhibitors (PPIs) may modulate outcomes with immune checkpoint inhibitors (ICIs) by altering the gut microbiome, altering the immune milieu, and affecting transporter interactions. We evaluated whether concomitant PPI use affects survival among patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab. Materials and Methods: We retrospectively included patients with metastatic NSCLC who received second-line nivolumab across five oncology centers (January 2020–June 2023). Patients were grouped as concomitant PPI users vs. non-users. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan–Meier method and compared with the log-rank test; multivariable Cox models assessed independent associations. Results: A total of 194 patients were screened, of whom 30 were excluded according to predefined criteria. The final analysis included 164 patients—85 PPI users and 79 non-users. Median OS was 26.1 months (95% CI 15.5–36.7) in PPI users and 29.3 months (22.2–36.4) in non-users; this difference was not statistically significant (p = 0.54). Median PFS was 6.2 months (3.7–8.6) in PPI users vs. 10.2 months (7.1–13.2) in non-users (p = 0.04). In multivariable analysis, absence of concomitant PPI use (No vs. Yes) was independently associated with longer PFS (HR = 0.52, 95% CI 0.24–0.89, p = 0.03), whereas PPI use was not associated with OS (HR = 0.96, 95% CI 0.67–1.61, p = 0.83). Conclusions: Concomitant PPI use during nivolumab therapy was associated with significantly shorter PFS and a numerical reduction in OS in real-world metastatic NSCLC. Where clinically feasible, the need for PPIs should be re-evaluated before and during ICI therapy.