Immune checkpoint blockers have revolutionized the first-line treatment of advanced non-small-cell lung cancer (NSCLC). Pembrolizumab, an anti-PD-1 monoclonal antibody, is a standard therapy either alone or in combination with chemotherapy (chemo-IO). The current study explores the efficacy and safety of pembrolizumab with carboplatin and weekly paclitaxel in a cohort of frail patients. A monocentric retrospective study was conducted between 22 September 2020 and 19 January 2023 regarding patients with stage IV NSCLC treated with chemo-IO combination: carboplatin (AUC 5 mg/mL/min; Q4W), weekly paclitaxel (90 mg/m on days 1, 8, and 15), and pembrolizumab (200 mg Q4W). The primary objective was real-world progression-free survival (rwPFS). Secondary objectives were overall survival (OS), toxicity profile, and outcomes based on histological subtype. A total of 34 patients (20 squamous and 14 non-squamous NSCLC) benefited from the chemo-IO regimen for frail patients; 41.9% had an ECOG-PS = 2. The median age was 75.5 years. We observed an overall response rate (ORR) of 55.9%. Notably, squamous NSCLC exhibited a significantly higher ORR (80%) than non-squamous NSCLC (21.4%); = 0.001. The median rw-PFS was 10.6 months (95% CI 6.0, NA), with 6- and 12-month rw-PFS rates of 69% and 45.8%, respectively. The median OS was not reached, with 12- and 18-month OS rates of 75.6% and 61.4%, respectively. The median number of maintenance cycles of pembrolizumab was 5 (0; 27). Nine patients (26.5%) experienced a toxicity related to chemotherapy leading to a reduction of the dose administered and, in five patients (14.7%), to the permanent discontinuation of chemotherapy. Six patients (17.6%) had an immune-related adverse event leading to the discontinuation of immunotherapy. Pembrolizumab plus carboplatin and weekly paclitaxel demonstrates promising efficacy and safety in frail patients with metastatic NSCLC, especially for ORR in sq-NSCLC. Prospective studies focusing on frail populations are warranted in order to validate these findings and optimize therapeutic strategies in the first-line setting.