Objective: To explore the role of TTYH3 gene in the occurrence and development of colorectal cancer (CRC) and its relationship with prognosis.Methods: Obtain RNA sequencing expression profiles and clinical pathological information of CRC patients from the TCGA database, R language screening for differentially expressed genes, exploring the prognostic role of TTYH3 in CRC through KM survival analysis. GO and KEGG enrichment analysis to explore the potential role of TTYH3 in CRC, MTT and colony formation experiments were conducted to investigate the effect of TTYH3 on the proliferation ability of CRC cells. Cox univariate and multivariate analysis to identify independent prognostic factors related to CRC survival, construct a nomogram to predict the survival rate of CRC 1, 3, 5 years.Results: TTYH3 was overexpressed in CRC tissues and cells (P<0.05), the overall survival rate of CRC patients with high expression of TTYH3 was lower (P<0.05), overexpression of TTYH3 could improve the proliferation ability of CRC cells, while knocking down TTYH3 expression could inhibit the proliferation ability of CRC cells. There was a statistically significant difference in TNM staging, tumor size, and lymph node metastasis between CRC patients with high and low expression of TTYH3 (P <0.05). Univariate Cox regression analysis determined that age (P=0.000), T stage (P<0.001), N stage (P<0.001), M stage (P<0.001), and TTYH3 expression (P<0.001) were correlated with prognosis. Multivariate Cox analysis showed that T stage (P=0.001), N stage (P=0.001), and TTYH3 expression (P<0.001) were independent prognostic factors related to prognosis. Construct a nomogram based on prognostic clinical factors (T and N stages), the survival calibration curve showed that the predicted overall survival rate of CRC patients at 1, 3, and 5 years by the column chart was in good agreement with the actual observation results.Conclusion: TTYH3 was associated with prognosis and played an important role in the occurrence and progression of human CRC. TTYH3 may become a new prognostic biomarker and therapeutic target for CRC.