Chemoresistance is a prevalent issue in cancer, resulting in a poor prognosis. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2), a key regulator in cellular antioxidant responses, is implicated in cell survival, proliferation, and chemoresistance. It represents a promising target for treating Hepatocellular carcinoma (HCC). The NRF2 activity has been recently revealed to be controlled by the ubiquitination process mediated by the KEAP1-CUL3 E3 ligase, highlighting the importance of deubiquitination regulation. However, the specific deubiquitinase (DUB) responsible for NRF2 in liver cancer remains unclear. In this study, we demonstrate that Ubiquitin-Specific Protease 37 (USP37) acts as a novel regulator of NRF2 protein. Mechanistically, USP37 modulates the stability of NRF2 through enzymatic activity-dependent deubiquitination. Additionally, USP37 interacts with NRF2 and facilitates its deubiquitination. Elevated USP37 levels were associated with higher levels of NRF2 protein in samples from human patients. Importantly, the knockdown of USP37 results in increased NRF2 degradation and enhances cellular sensitivity to chemotherapy. Overall, our findings manifested the significant involvement of the USP37-NRF2 axis in regulating therapeutic interventions for HCC.