Nonalcoholic fatty liver disease (NAFLD) is presently one of the most widespread chronic liver disorders globally. This research aimed to investigate the efficacy of using a combination of silymarin and ethyl gallate to prevent NAFLD triggered by a high-fat diet. The NAFLD model was created by feeding C57BL/6 mice a high-fat diet for 16 weeks. Silymarin alone at a high dose (100 mg/kg), ethyl gallate alone at a high dose (40 mg/kg), and silymarin with ethyl gallate at a low dose (50 mg/kg and 20 mg/kg, respectively) were administered alongside a high-fat diet. The findings of this study revealed that administration of silymarin with ethyl gallate could cause a notable decrease in body weight. The liver weight and liver index, the steatosis, and the lobular inflammation were also alleviated. Moreover, the serum levels of transaminases, alkaline phosphatase (ALP), and triglycerides (TG) were all significantly decreased in the combination treatment group. The hepatic TG and sterol regulatory element-binding protein 1C (SREBP-1C) levels were also notably low. Furthermore, there was a significant decrease in the levels of nuclear factor kappa B (NF-κB) and tumor necrosis factor alpha (TNF-α) and oxidative stress in the combination treatment group. In conclusion, silymarin combined with ethyl gallate can effectively protect against NAFLD induced by a high-fat diet by controlling lipid metabolism, reducing oxidative stress, and attenuating liver inflammation, collectively demonstrating the therapeutic potential of this phytochemical combination as a promising pharmacological strategy for the prevention and management of NAFLD.