Abstract: Oral liver-targeting nano-drug delivery system is the most potential drug delivery method which has the advantages of good drug compliance, low side effects, and high safety. However, the biological and physiological barriers in the gastrointestinal tract and liver severely hinder the oral absorption and accumulation of drug carriers in the liver lesions. This review first describes the main biological and physiological barriers encountered by the oral liver-targeted nano-drug delivery system during the drug delivery period. Meanwhile, this article summarizes oral liver-targeting drug carriers in recent years. In addition, the research progress of oral liver-targeted nano-drug delivery system in the treatment of liver-related diseases is introduced, which provides ideas for the development of oral liver-targeting nano-drug delivery system in the liver-related disease treatment.