Hepatic steatosis is a common pathological change of liver that manifests as abnormal lipid accumulation. Epidemiological findings support that diseases such as obesity, diabetes, and hyperlipidemia are mostly accompanied by the development of hepatic steatosis. By screening the disease targets of several traditional Chinese medicines (TCMs) with lipid-reducing effects (hawthorn, semen cassiae, etc.) through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), we found that peroxisome-activated receptor gamma (PPAR-γ) is involved in regulating several lipid metabolism-related signaling pathways. Further experiments confirmed that PPAR-γ was correlated with aggravated endoplasmic reticulum (ER) stress in overnutrition-induced hepatic steatosis. The stimulation of hepatocytes by abnormal lipid metabolism signals causes an imbalance in ER homeostasis, which subsequently exacerbates hepatocyte lipid abnormalities. The inhibition of glucose regulatory protein 78 (GRP78, a master regulator of ER homeostasis) was effective in reducing hepatocyte PPAR-γ and lipid synthesis levels. In fact, the hawthorn/semen cassiae treatment effectively downregulated hepatocyte ER stress in high-fat-diet fed rats and reduced the PPAR-γ expression as well as related lipid synthesis. Herein, we confirmed that TCMs characterized by natural lipid-lowering effectively target hepatic PPAR-γ and GRP78, improve ER stress, and have a protective effect against obesity-related hepatic steatosis.