The global prevalence of liver diseases is continuously on the rise, with alcoholic liver disease, metabolic-related fatty liver disease, autoimmune liver disease, drug-induced liver injury, and liver fibrosis/cirrhosis becoming prominent public health issues. Traditional chemical drugs have significant side effects and act on a single target, while food-medicine homologous substances, which are widely available and have high safety, demonstrate unique value in the prevention and treatment of various liver diseases due to their multi-component synergistic effects. This review summarizes the protective effects of food-medicine homologous substances from plants, animals and fungi on various liver injury models with a focus on their synergistic effects. Based on the pathological process of liver injury, this article reconstructs the mechanism system and elaborates on the characteristics of cross-talk and synergistic enhancement among components and pathways. It also discusses the current challenges for the applications of food-medicine homologous substances. This review aims to provide a scientific basis for the collaborative development of food-medicine homologous substances and natural intervention strategies for liver diseases and to offer references for innovative research in the fields of food therapy, medicine, and health care.