Objective：To construct a new model for predicting the outcomes and therapeutic efficacy of colorectal cancer（CRC）. Methods：Firstly，the univariate analysis and the least absolute shrinkage and selection operator（LASSO）-Cox regression analysis were used to train the GSE39582 dataset to construct a prognostic signature of colorectal cancer（PSCRC），and external datasets CRC_TCGA and GSE17536 were used to validate PSCRC. The correlations of PSCRC with clinical indicators，tumor immune microenvironment and immune cells infiltration were evaluated，and the molecular function of PSCRC was analyzed by gene set enrichment analysis（GSEA）. Next，seven factors，such as PSCRC and clinical stage，were integrated to draw a prognostic nomogram， and the prognostic effect was evaluated by the decision curve analysis（DCA）. Finally，the efficacy of immunotherapy and chemotherapy was predicted. Results：We constructed a PSCRC，which was validated by two external datasets，confirming its high prognostic sensitivity and specificity. TNM staging significantly affected the risk scores of PSCRC（all P ＜ 0.001）；PSCRC showed significantly positively correlations with tumor microenvironment matrix（TME）score，immune score，and ESTIMATE score（all P ＜ 0.001），significantly positive correlations with infiltrations such as neutrophils（all P ＜ 0.05），and significantly negative correlations with infiltrations like activated memory CD4 ⁺ T cells（all P ＜ 0.01）. In addition，the GSEA analysis indicated that PSCRC might participate in oxidative phosphorylation，angiogenesis，hypoxia and inflammatory response. Importantly，the newly constructed model showed a good prognostic ability，with a C-index of 0.765 and a 95% confidence interval（CI）of 0.747 to 0.783（P ＜ 0.001）. Finally，in the three datasets，the therapy prediction results revealed that the low-risk scoring group had a high response rate to immunotherapy （all P ＜ 0.001）；PSCRC was significantly negatively correlated with the half inhibitory concentration（IC₅₀）of chemotherapy drugs such as imatinib，dasatinib，and pazopanib（all P ＜ 0.001），and significantly positively correlated with the IC₅₀ of metformin，sorafenib and other drugs（all P ＜0.001）. Conclusion：We construct a PSCRC，which provides a robust model for CRC prognosis. and also offers a potential marker for predicting treatment.