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Colorectal cancer (CRC) is a high burden disease with several genes involved in tumor progression. The aim of the present study was to identify, generate and clinically validate a novel gene signature to improve prediction of overall survival (OS) to effectively manage colorectal cancer. We explored The Cancer Genome Atlas (TCGA), COAD and READ datasets (597 samples) from The Protein Atlas (TPA) database to extract a total of 595 candidate genes. In parallel, we identified 29 genes with perturbations in &gt; 6 cancers which are also affected in CRC. These genes were entered in cBioportal to generate a 17 gene panel with highest perturbations. For clinical validation, this gene panel was tested on the FFPE tissues of colorectal cancer patients (88 patients) using Nanostring analysis. Using multivariate analysis, a high prognostic score (composite 4 gene signature&#8212;<i>DPP7/2</i>, <i>YWHAB</i>, <i>MCM4</i> and <i>FBXO46</i>) was found to be a significant predictor of poor prognosis in CRC patients (HR: 3.42, 95% CI: 1.71&#8722;7.94, <i>p</i> &lt; 0.001 *) along with stage (HR: 4.56, 95% CI: 1.35&#8722;19.15, <i>p</i> = 0.01 *). The Kaplan-Meier analysis also segregated patients on the basis of prognostic score (log-rank test, <i>p</i> = 0.001 *). The external validation using GEO dataset (GSE38832, 122 patients) corroborated the prognostic score (HR: 2.7, 95% CI: 1.99&#8722;3.73, <i>p</i> &lt; 0.001 *). Additionally, higher score was able to differentiate stage II and III patients (130 patients) on the basis of OS (HR: 2.5, 95% CI: 1.78&#8722;3.63, <i>p</i> &lt; 0.001 *). Overall, our results identify a novel 4 gene prognostic signature that has clinical utility in colorectal cancer.