Elevated evidence has reported the important role of oxidative stress injury and inflammatory response in the progression of colitis. Tumor Suppressor TSBF1, TRIM59, is a ubiquitin E3 ligase and mediates immune response. However, the underlying molecular function of TRIM59 on regulation of colitis is still not understood. In the current study, we identify the TRIM59 as a critical and novel endogenous suppressor of kelch-like ECH-associated protein 1 (KEAP1), and we also determine that TRIM59 is a KEAP1-interacting partner protein that catalyses its ubiquitination and degradation in intestinal epithelial cells (IEC). Moreover, IEC-specific loss of the Trim59 disrupts colon metabolic homeostasis, accompanied by intestinal oxidative stress injury, elevated endogenous reactive oxygen species (ROS) production and pro-inflammatory cytokines release, significantly promotes acute or chronic colitis progression. Conversely, transgenic mice with Trim59 overexpression by adeno-associated virus (AAV)-induced Trim59 gene therapeutics mitigates colitis in acute or chronic colitis rodent models and in vitro experiments. Mechanistically, in response to onset of colitis, TRIM59 directly interacts with KEAP1 and promotes ubiquitin-proteasome degradation, thus results in NRF2 activation and its downstream cascade anti-oxidative stress-related pathway activation, which facilitates anti-oxidant defense and reduces tissue damage. All the findings elucidated the potential role of TRIM59 in colitis progression by mediating KEAP1 deactivation and degradation, and could be considered as a therapeutic target for the treatment of such disease.