Background: Pembrolizumab is the recommended first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) and a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥50% without driver mutations. However, its efficacy and safety for patients ≥75 years has not been prospectively investigated; this was the aim of this study. Methods: This multi-center and open-label single-arm phase II study was conducted at 12 institutions. Chemotherapy-naïve patients with advanced NSCLC and a PD-L1 TPS of ≥50% without EGFR mutations or translocation of the ALK received pembrolizumab (200 mg) every 3 weeks. The primary endpoint was progression-free survival (PFS) with a threshold of 4.3 months. The secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety. Quality of life (QOL) was assessed using EORTC QLQ-C30 and EORTC QLQ-LC13. The patients completed the questionnaires immediately after providing informed consent, and also before the third, sixth, twelfth, eighteenth, and twenty-fourth treatment cycles. Results: Twenty-six patients were enrolled between October 2017 and March 2020. The median PFS was 9.6 (95% confidence interval [CI], 2.1–20.6) months. The lower limit of the 95% CI did not exceed the target. The median OS was 21.6 (95% CI, 15.1–not reached) months.The ORR and DCR were 41.7% (24.5–61.2) and 70.8% (50.8–85.1), respectively. The proportion of patients with Grade ≥3 treatment-related adverse events was 15.4%. The Score of Global Health Status/QOL, symptom scales and/or items, and functioning scales of EORTC QLQ-C30 and EORTC QLQ-LC13 did not change significantly during the treatment. Conclusions: This study showed pembrolizumab was tolerable treatment for the elderly patients. Although the primary endpoint, the median PFS (9.6 months) was slightly shorter than that (10.3 months) of the previous phase III study (KEYNOTE-024 study), the median PFS, did not achieve the expected value. Clinical trial information: UMIN000040474.