Abstract: Objective: To investigate the effect of GDP dissociation inhibitor 2(GDI2) on the proliferation, migration, invasion, apoptosis and cell cycle of colorectal cancer(CRC) cells and its mechanism. Methods: TCGA database was used to analyze the expression of GDI2 mRNA in CRC tumor tissues. CRC cells were divided into sh-NC group and sh-GDI2 group. Cell counting kit-8(CCK-8) assay was used to detect the cell viability, colony formation assay was used to detect the cell proliferation, Transwell assay was used to detect the cell migration and invasion, flow cytometry was used to detect the cell apoptosis and cycle, real-time fluorescence quantitative PCR(RT-qPCR) was used to detect the GDI2 gene expression and western blotting was used to detect the expression of GDI2 protein and key factors of nerve growth factor receptor(p75NTR) pathway(IKK, p-NF-κB and pIκB). The nude mouse model of xenograft tumor was constructed to observe the effect of GDI2 on CRC tumor growth. Results: Compared with the adjacent normal tissues and normal colonic epithelial cells, the expression of GDI2 was up-regulated in tumor tissues and cell lines of CRC patients(P<0.05). The sh-GDI2 could inhibit the proliferation, migration, invasion, cell cycle progression, and promote the apoptosis of CRC cells(all P<0.05).Compared with the sh-NC group, the expression of p75NTR protein was up-regulated, and the expression of IKK, p-Nf-κB and p-IκB protein was down-regulated in the sh-GDI2 group(all P<0.05). Knockdown of GDI2 significantly inhibited the growth of CRC tumors in nude mice(P<0.05). Conclusion: Knockdown of GDI2 may inhibit the proliferation, invasion and migration and promote the apoptosis of CRC cells through p75NTR signaling pathway.