Nonalcoholic steatohepatitis (NASH) is an unmet clinical challenge due to the rapid increase in its occurrence but the lack of approved drugs to treat it. Further unraveling of the molecular mechanisms underlying NASH may identify potential successful drug targets for this condition. Here, we identified TNFAIP3 interacting protein 3 (TNIP3) as a novel inhibitor of NASH. Hepatocyte-specific TNIP3 transgenic overexpression attenuates NASH in two dietary models in mice. Mechanistically, this inhibitory effect of TNIP3 is independent of its conventional role as an inhibitor of TNFAIP3. Rather, TNIP3 directly interacts with TAK1 and inhibits its ubiquitination and activation by the E3 ligase TRIM8 in hepatocytes in response to metabolic stress. Notably, adenovirus-mediated TNIP3 expression in the liver substantially blocks NASH progression in mice. These results suggest that TNIP3 may be a promising therapeutic target for NASH management.