Colorectal cancer (CRC) is the most common malignancy in the digestive system, with a lower 5-year overall survival rate. There is increasing evidence showing that RNA modification regulators such as m1A, m5C, m6A, and m7G play crucial roles in tumor progression. However, the prognostic role of integrated m6A/m5C/m1A/m7G methylation modifications in CRC has not been reported and requires further investigation. Five cohorts with 989 samples were first retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Then, Three m6A/m1A/m5C/m7G-associated molecular subtypes were identified in the TCGA cohort via the consensus clustering analysis, and 1710 co-expression module genes associated with subtypes were obtained from weighted gene co-expression network analysis (WGCNA) results. After conducting univariate Cox analysis in each cohort and retaining common genes, an RNA methylation-related signature (RMS) was developed through the combination of 101 algorithms. The RMS exhibited strong accuracy and robustness in predicting survival outcomes across distinct cohorts (TCGA, GSE17536, GSE17537, GSE29612, and GSE38832) and demonstrated good performance compared with previously reported risk signatures. Additionally, the RMS was identified as an independent prognostic factor for overall survival in the TCGA, GSE17536, GSE17537, GSE29612, and GSE38832 cohorts. The patients were then stratified into high and low-risk groups based on the median risk score across the five cohorts. Compared to the high-risk groups, the low-risk group showed an increased immune cell infiltration level and showed more benefit from immunotherapy and chemotherapy drugs. Moreover, six drugs (KU-0063794, temozolomide, DNMDP, ML162, SJ-172550, ML050) from the Cancer Therapeutics Response Portal (CTRP) and five drugs (BIBX-1382, lomitapide, ZLN005, PPT, panobinostat) from the PRSM database were identified for the high-risk group patients. By integrating data from the TCGA database and the Cancer Cell Line Encyclopedia (CCLE) database, a potential therapeutic target named TERT was identified for the high-risk group of patients. The single-cell results indicated that TERT was highly expressed in epithelial cells. Overall, our developed RMS can accurately predict patients survival outcomes and immunotherapy response, indicating promising application in clinical practice. These findings may offer guidance for the prognosis and personalized treatment of CRC.