Background: Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancer cases, and most patients present with advanced disease at diagnosis. While chemotherapy has been the cornerstone of treatment, recent advances in immunotherapy, particularly immune checkpoint inhibitors (ICIs), have significantly improved outcomes. This study aims to evaluate the clinical efficacy of combining immunotherapy with chemotherapy in advanced NSCLC compared to chemotherapy alone. Methods: A total of 160 patients with stage IIIb or IV NSCLC were enrolled in a multicenter prospective cohort study. Participants were divided into two treatment groups: combination therapy (platinum-doublet chemotherapy plus PD-1/PD-L1 inhibitors, n=80) and chemotherapy alone (n=80). Primary endpoints included progression-free survival (PFS) and overall survival (OS), while secondary endpoints were objective response rate (ORR) and safety profiles. Kaplan–Meier survival curves, Cox proportional hazards models, and logistic regression analyses were used to assess clinical outcomes. Results: The combination therapy group showed a significant improvement in median PFS (9.8 vs. 5.4 months, p < 0.001) and OS (18.1 vs. 11.2 months, p = 0.002) compared to chemotherapy alone. ORR was also higher in the combination group (52.5% vs. 30.0%, p = 0.003). Treatment-related adverse events (TRAEs) were more frequent in the combination group but remained manageable. Grade 3–4 toxicities occurred in 28.8% of patients receiving combination therapy versus 21.3% in the chemotherapy group. Conclusion:Combining immunotherapy with chemotherapy significantly improves survival and tumor response rates in patients with advanced NSCLC without unacceptable toxicity. This approach should be considered a frontline standard in eligible patients, pending further long-term evaluation.