New cases of gastric cancer rank fifth in malignant tumors, while colorectal cancer is the third most common malignant tumor and the fourth most common cause of cancer death in the world. The dynamic balance of histone acetylation is jointly maintained by histone acetyltransferase (HAT) and histone deacetylase, (HDAC) enzyme families. HDAC can remove acetyl groups from lysine, thus inhibiting gene transcription. However, abnormally high expression of HDAC can induce normal cells to turn cancerous and participate in its development, proliferation, invasion and metastasis. Targeted inhibition of HDAC has been proved to have anti-tumor effect. Histone deacetylase inhibitors (HDACi) can inhibit the expression and activity of HDAC. Moreover, HDAC plays a potent anti-tumor role by influencing the level of cell reactive oxygen species, blocking cell cycle, promoting repair of damaged DNA, resisting angiogenesis, influencing cell signal pathways, inducing autophagy apoptosis and increasing the sensitivity of cells to chemoradiotherapy drugs. HDAC expression is increased in gastric cancer and colorectal cancer, and HDACi also shows good results in the study of gastrointestinal tumors. Since the catalytic core functions of class I, II and IV HDAC all depend on Zn2+, most HDACi contain Zn2+ chelating groups. SAHA and TSA in hydroxamic acid inhibitors have good anti-tumor effects when administered alone in small doses. However, later clinical studies found that SAHA has poor clinical efficacy in treating gastric cancer and colorectal cancer due to its low activity. The activity of TSA has been improved, but its selectivity to HDAC is still low, benzamide HDACi is improved in selectivity, but it cannot be only targeted at specific subtypes of HDAC. The selectivity of late cyclic peptides and newly reported HDACi is gradually increased, but it is only limited to animal and cell experimental stages, and the above-mentioned HDACi can combine with other metalloenzymes in addition to Zn2+, thus lacking absolute specificity. Therefore, most HDACi has caused side effects at a very small dose. As the occurrence and development of tumors involve multiple steps and factors, a single target often cannot effectively kill cancer cells and is prone to drug resistance. Combination of multiple targets has stronger anti-cancer effect than a single target, and can even reduce the occurrence of drug resistance. However, sometimes adverse reactions caused by drug interaction may occur when drugs are used in combination. In order to avoid drug interaction, based on the concept of pharmacophore splicing, researchers designed and synthesized a new multitarget inhibitor by reasonably splicing HDACi active groups and active groups of other drugs with different action targets. Studies have proved that multi-target inhibitors not only avoid drug interactions, but also improve drug effects. This paper introduces in turn the research progress of HDACi and HDACi-related multi-inhibitors in gastrointestinal tumors.