Hypoxia-related gene (HRG) expression is associated with survival outcomes of colorectal cancer (CRC). Our aim was developing a nomogram predicting CRC overall survival (OS) with HRGs and clinicopathological factors. The Cancer Genome Atlas (TCGA) database was used as discovery cohort and two Gene Expression Omnibus databases (GSE39582 and GSE41258) served as validation cohorts. A genetic risk score model prognosticating OS was developed using mRNA expression level of HRGs. Nomogram predicting OS was developed using genetic risk score model and clinicopathological variables. The genetic risk score model included four HRGs (HSPA1L, PUM1, UBE2D2, and HSP27) and successfully prognosticated OS of discovery and two validation cohorts (p < 0.001 for TCGA discovery set, p < 0.003 for the GSE39582 and p = 0.042 for the GSE41258 datasets). Nomogram included genetic risk score, age, and TNM stage. Harrell’s concordance indexes of the nomogram were higher than those of TNM stage alone in the discovery set (0.77 vs. 0.69, p < 0.001), GSE39582 (0.65 vs. 0.63, p < 0.001), and GSE41258 datasets (0.78 vs. 0.77, p < 0.001). Our nomogram successfully predicted OS of CRC patients. The mRNA expression level of the HRGs might be useful as an ancillary marker for prognosticating CRC outcome.