Patients with diabetes, obesity, and hyperlipidemia are all high-risk groups for fatty liver; however, the mechanism of fatty liver formation is not completely understood. Studies have indicated that abnormal fat metabolism, oxidative stress, and insulin resistance are positively correlated with peroxidation and abnormal cytokine production. Recent studies have revealed that Solanum nigrum extracts (SNE) possess anti-inflammatory, antioxidation, antihyperlipidemia, and liver protection abilities. Therefore, the present study investigated the in vivo and in vitro effects of an SNE on nonalcoholic fatty liver (NAFL)-induced hepatitis. In vivo data demonstrated that the SNE reduced blood triglyceride, sugar, and cholesterol levels, as well as fat accumulation, oxidative stress, and lipid peroxidation in high-fat-diet-treated mice. The results indicated that the SNE downregulated the expression of fatty acid synthase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), and sterol regulatory element-binding proteins (SREBPs) through the AMP-activated protein kinase (AMPK) pathway and upregulated the expression of carnitine palmitoyltransferase 1 (CPT1) and peroxisome proliferator-activated receptor alpha. Furthermore, we prepared a Solanum nigrum polyphenol extract (SNPE) from the SNE; the SNPE reduced hepatic lipid (oleic acid) accumulation. Therefore, SNE have the potential to alleviate NAFL-induced hepatitis, and polyphenolic compounds are the main components of SNE. Moreover, SNE can be used to develop health-food products for preventing NAFL disease.