Background: This study aimed to explore the influence of endothelial cell-specific molecule 1 (ESM1) expression on colorectal cancer (CRC) cells and preliminarily analyze its possible mechanism, so as to lay a foundation for research about potential biological targets of CRC.Methods: First, CRC cells were transfected with ESM1-negative control (NC), ESM1-mimic and ESM1-inhibitor and randomly assigned to ESM1-NC group, ESM1-mimic group and ESM1-inhibitor group, respectively. Then the cells were harvested at 48 h after transfection for subsequent experiments.Results: The results manifested that after up-regulation of ESM1, the distance of CRC SW480 and SW620 cell lines migrating to the scratch center rose notably, and the number of migrating cells, basement membrane-penetrating cells, colonies formed and angiogenesis was increased overtly, indicating that ESM1 overexpression can promote tumor angiogenesis in CRC and accelerate tumor progression. Combined with results of bioinformatics analysis, the molecular mechanism by which ESM1 promoted tumor angiogenesis in CRC and accelerated tumor progression was explored through suppressing the protein expression of phosphatidylinositol 3-kinase (PI3K). Western blotting revealed that after intervention with PI3K inhibitor, the protein expressions of phosphorylated PI3K (p-PI3K), phosphorylated protein kinase B (p-Akt) and phosphorylated mammalian target of rapamycin (p-mTOR) were decreased evidently, and the protein expressions of matrix metalloproteinase-2 (MMP-2), MMP-3, MMP-9, Cyclin D1, Cyclin A2, VEGF, COX-2 and HIF-1α subsequently declined.Conclusion: ESM1 may promote angiogenesis in CRC by activating the PI3K/Akt/mTOR pathway, thus accelerating tumor progression.