This study delves into the intricate relationship between mutations in the SWI/SNF chromatin remodeling complex and the activation of the KEAP1-NRF2 signaling pathway across various cancer types. It highlights a significant association between ARID1A/B mutations and NRF2 transcriptional activity specifically in head and neck squamous carcinomas (HNSC), suggesting a pivotal role of ARID1A inactivation in HPV-negative HNSC. The research uncovers that different cancer types exhibit a notable link between NRF2 signaling and mutations in specific SWI/SNF complex components, with distinct effects observed for BAF and PBAF mutations on NRF2 signaling polarity. This work underscores a context-dependent functional connection between SWI/SNF and NRF2 mutations across human cancers, proposing a novel area of investigation into how these mutations influence cancer progression and survival. The findings emphasize the importance of understanding the tumor-specific impacts of these mutations, potentially guiding targeted therapeutic strategies.