Background and Purpose: Diosmetin (Dios) exerted a hepatoprotective effect against nonalcoholic steatohepatitis (NASH), but few reports interpreted clearly that the alleviation of Dios against NASH were associated with the inhibition of signal transducers and activators of transcription 1 (STAT1) and macrophage chemotactic ligand 10 (CXCL10). Meanwhile, the mechanism of Dios involved with STAT1/CXCL10 mediated pathway was unknown yet. Experimental Approach: Here, high-fat diet (HFD) and palmitic acid (PA) were used to induced NASH model in mice and HepG2 cells, respectively. The liver RNA-Seq was used to reveal the key targets interfered by Dios. The impacts of Dios on the expressions of STAT1, CXCL10 and the levels of genes and proteins associated with lipogenesis and inflammation were measured by qRT-PCR and western blot assays. The STAT1 inhibitor, STAT1 overexpression plasmid, and CXCL10 siRNA were utilized to clarify the mechanism of Dios against NASH through STAT1 / CXCL10. Key Results: Dios could reduce functional parameters and morphological changes in HepG2 cells and NASH mice. Additionally, Dios alleviated the expressions of key targets STAT1 and CXCL10, and their downstream proteins involved with lipogenesis and inflammation. Interestingly, NASH was ameliorated in STAT1-inhibited mice and HepG2 cells. Unfortunately, transfecting HepG2 cells with STAT1 over-expression plasmid aggravated the development of NASH and reduced Dios-conferred hepatoprotective effect. Conclusions and Implications: The alleviation of Dios against NASH was through mediation of lipogenesis and inflammatory response via STAT1/CXCL10-dependent pathway. Therefore, Dios has good hepatoprotective effects and potentiality as a promising therapeutic agent for NASH in clinical application.