Nuclear factor erythroid 2-related factor 2 (NRF2) protein expression promotes cancer progression in non-small cell lung cancer (NSCLC). However, its role in the clinical setting has not been established. We retrospectively analyzed data from 304 patients with surgically removed NSCLC. Multiplex antibody staining of NRF2 and thioredoxin reductase 1 (TrxR1) was conducted and scored in cytokeratin-positive (CK+) cells within the whole-tissue core as well as the tumor and stromal compartments of each tissue microarray (TMA) core. A high density of NRF2+/CK+ cells in the whole-tissue core compartment was correlated with a higher risk of central nervous system (CNS) relapse OR = 7.36 (95% CI: 1.64–33.06). The multivariate analysis showed an OR = 8.00 (95% CI: 1.70–37.60) for CNS relapse in NRF2+/CK+ high-density cases. The density of TrxR1+/CK+ cells failed to show any statistically significant risk of relapse. The OS analyses for NRF2+/CK+ and TrxR1+/CK+ cell density failed to show any statistical significance. This is the first study to report a correlation between NRF2+/CK+ cell density and the risk of CNS relapse in early-stage NSCLC. The results of our study may impact the follow-up strategy for early-stage NSCLC patients and eventually improve their prognosis.