There is a lack of markers for predicting favorable outcomes after pembrolizumab therapy in patients with non-small cell lung cancer (NSCLC) with programmed death ligand-1 (PD-L1) expression ≥ 50%. This retrospective study examined the prognostic significance of 2-deoxy-2-[18F] fluoro-D-glucose (18F-FDG) uptake as a predictive marker of first-line pembrolizumab. Forty-eight patients with previously untreated NSCLC and PD-L1 expression levels ≥ 50% who underwent 18F-FDG-positron emission tomography (PET) just before administration of pembrolizumab monotherapy were eligible and underwent assessment of metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum of standardized uptake value (SUVmax) on 18F-FDG uptake. The objective response rate, median progression-free survival, and median overall survival were 51.1%, 7.1 months, and 18.6 months, respectively. In univariate survival analyses, high MTV was barely a significant prognostic predictor and was confirmed as an independent factor linked to worse outcomes in multivariate analysis, predominantly in patients with a histological diagnosis of adenocarcinoma. A high MTV was significantly associated with distant metastases (especially bone metastasis), C-reactive protein (CRP) level, and PD-L1 expression ≥ 75%. Metabolic tumor activity assessed as MTV from 18F-FDG uptake predicted the prognosis after first-line pembrolizumab treatment in patients with NSCLC and PD-L1 expression ≥ 50%, especially for adenocarcinoma.