Background Epeleuton is 15‐hydroxy eicosapentaenoic acid ethyl ester, a second‐generation synthetic n‐3 fatty acid derivative of eicosapentaenoic acid. The primary objective was to assess the effect of epeleuton on markers of nonalcoholic fatty liver disease (NAFLD) with post hoc analyses of cardiometabolic markers. Methods and Results In a multicenter, randomized, double‐blind, placebo‐controlled trial, 96 adults with nonalcoholic fatty liver disease and body mass index 25 to 40 were randomized in a 1:1:1 ratio to receive epeleuton 2 g/day, epeleuton 1 g/day, or placebo for 16 weeks. A total of 27% of patients had diabetes mellitus. Primary end points of changes in alanine aminotransferase and liver stiffness did not improve at week 16. Secondary and post hoc analyses investigated changes in cardiometabolic markers. Epeleuton 2 g/day significantly decreased triglycerides, very‐low‐density lipoprotein cholesterol, and total cholesterol without increasing low‐density lipoprotein cholesterol. Despite a low mean baseline hemoglobin A1C (HbA 1C ; 6.3±1.3%), epeleuton 2 g/day significantly decreased HbA 1c (−0.4%; P =0.026). Among patients with baseline HbA 1c >6.5%, epeleuton 2 g/day decreased HbA 1c by 1.1% ( P =0.047; n=26). Consistent dose‐dependent reductions were observed for fasting plasma glucose, insulin, and insulin resistance indices. Epeleuton 2 g/day decreased circulating markers of cardiovascular risk and endothelial dysfunction. Epeleuton was well tolerated, with a safety profile not different from placebo. Conclusions While epeleuton did not meet its primary end points on alanine aminotransferase or liver stiffness, it significantly decreased triglycerides, HbA 1C , plasma glucose, and inflammatory markers. These data suggest epeleuton may have potential for cardiovascular risk reduction and nonalcoholic fatty liver disease by simultaneously targeting hypertriglyceridemia, hyperglycemia, and systemic inflammation. Further trials are planned. Registration URL: https://www.clini​caltr​ials.gov ; Unique identifier: NCT02941549.