Liver disorders like hepatitis, cirrhosis, and hepatocellular carcinoma present a significant global health challenge, with high morbidity and mortality rates. Key factors contributing to liver disorders include inflammation, oxidative stress, and apoptosis. Due to their multifaceted action, natural compounds are promising candidates for mitigating liver-related disorders. Research studies revealed the antioxidant, anti-inflammatory, and detoxifying properties of natural compounds like curcumin, glycyrrhizin, and silymarin and their potential for liver detoxification and protection. With advancements in nanotechnology in drug delivery, natural compounds have improved stability and targetability, thereby enhancing their bioavailability and therapeutic efficiency. Further, recent advancements in genomics and an increased understanding of genetic factors influencing liver disorders and the hepatoprotective effects of natural agents made way for personalized medicine. Moreover, combinatorial therapy with natural products, synthetic drugs, or other natural agents has improved therapeutic outcomes. Even though clinical trials have confirmed the efficiency of natural compounds as hepatoprotective agents, several challenges remain unanswered in their translation to clinical practice. Therefore, it is logical to integrate natural compounds with nanotechnology and genomics to further advance hepatoprotection. This review gives an overview of the substantial progress made in the field of hepatoprotection, with specific emphasis on natural compounds and their integration with nanotechnology and genomics. This provides valuable insights for future research and innovations in developing therapeutic strategies for liver disorders.