Liraglutide has been demonstrated to alleviate hepatic steatosis in clinical practice, but the underlying mechanism remains unclear. Our previous study indicated that the HIF-2α/PPARα pathway was involved in hepatic lipid accumulation induced by hypoxia.We aimed to investigate whether liraglutide could alleviate lipid-induced hepatic steatosis via the HIF-2α/PPARα pathway. Whole-body HIF-2α heterozygous knockout (HIF-2α) mice and littermate wild-type (WT) mice were successfully established. Male mice challenged with a high-fat diet were treated with liraglutide (0.6 mg/kg/d) or normal saline by intraperitoneal injection for 4 weeks. We observed that, compared with WT mice, many indicators of HIF-2α mice improved, including GTT, ITT, fasting blood glucose, body weight, liver weight, and lipid profile in serum or liver lipid deposition, and the expression level of PPARα, mitochondrial function genes, and fatty acid oxidation genes were upregulated, while those of HIF-2α and lipogenesis genes were downregulated significantly. After liraglutide treatment in WT mice, we found that significant improvements were observed in the fat mass, GTT, ITT, fasting blood glucose, body weight, liver weight, lipid profile in serum or liver lipid deposition; the β-oxidation genes were upregulated and the lipogenesis genes were downregulated; and the abundance of intestinal Akkermansia muciniphila increased significantly. However, the effects of liraglutide on WT mice were not observed in HIF-2α mice. In addition, in the HepG2 steatotic hepatocyte model, liraglutide alleviated lipid deposits by repressing lipid synthesis and enhancing fatty acid β-oxidation, which were substantially suppressed by the HIF-2α modulators. Therefore, the HIF-2α/PPARα pathway is essential for liraglutide-alleviated lipid-induced hepatic steatosis.