Monoacylglycerol acyltransferase 2 (MGAT2) is an important enzyme highly expressed in the human small intestine and liver for the regulation of triglyceride absorption and homeostasis. We report that treatment with BMS-963272, a potent and selective MGAT2 inhibitor, decreased inflammation and fibrosis in CDAHFD and STAM, two murine nonalcoholic steatohepatitis (NASH) models. In high-fat-diet-treated cynomolgus monkeys, in contrast to a selective diacylglycerol acyltransferase 1 (DGAT1) inhibitor, BMS-963272 did not cause diarrhea. In a Phase 1 multiple-dose trial of healthy human adults with obesity (NCT04116632), BMS-963272 was safe and well tolerated with no treatment discontinuations due to adverse events. Consistent with the findings in rodent models, BMS-963272 elevated plasma long-chain dicarboxylic acid, indicating robust pharmacodynamic biomarker modulation; increased gut hormones GLP-1 and PYY; and decreased body weight in human subjects. These data suggest MGAT2 inhibition is a promising therapeutic opportunity for NASH, a disease with high unmet medical needs. Display omitted •MGAT2 inhibitor BMS-963272 decreased inflammation and fibrosis in murine NASH models•BMS-963272 increased PYY and FGF-21 and decreased body weight in human subjects•Elevation of long-chain DCAs is a specific PD biomarker for MGAT2 inhibitors•MGAT2 inhibition is a promising approach for the treatment of NASH Cheng et al. demonstrate that MGAT2 inhibitor BMS-963272 decreased inflammation and fibrosis in CDAHFD and STAM mice and body weight in human obese subjects, which is consistent with elevation of gut hormone PYY and GLP-1 levels. Long-chain DCAs can serve as a specific translational PD biomarker for MGAT2 inhibitors.