Immune checkpoint inhibitors have revolutionized the treatment landscape of non-small cell lung cancer; however, durable benefits are achieved in only a subset of patients. This variability in outcomes underscores the need for combination strategies that modulate immunity at a systemic level, beyond the tumor microenvironment. Bojungikki-Tang (BJIKT), a traditional multi-herbal formula, has demonstrated synergistic anti-tumor effects with immune checkpoint inhibitors in preclinical models. Herein, we evaluated its clinical potential by investigating the impact of BJIKT on systemic immunity in patients with advanced non-small cell lung cancer receiving atezolizumab (anti-PD-L1). We conducted transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) from 19 patients in a randomized clinical study, comparing BJIKT plus atezolizumab (n = 12) with placebo plus atezolizumab (n = 7). BJIKT co-treatment induced a distinct transcriptional program enriched for CD8+ T-cell activation, natural killer (NK) cell-mediated cytotoxicity, and type I/II interferon signaling. Using machine learning, we identified a four-gene signature comprising IL1R2 and ETS2 down-regulation, concurrent with TUSC2 and S1PR2 up-regulation, that reliably discriminated patients receiving BJIKT. These data support a mechanistic rationale for BJIKT as a systems-level immunomodulator during immune checkpoint inhibitor therapy, and identify these genes as a practical marker set for noninvasive monitoring and future clinical validation.