Colorectal cancer (CRC) is one of the most prevalent and deadliest malignancies in the world.The microarray dataset GSE87211 has been re-analyzed in the present study through a multi-layered bioinformatics approach to identify the CRC associated hub genes. GSE87211 dataset was retrieved and GEO2R was implemented for the identification of differentially expressed genes (DEGs). STRING tool was used to construct the protein-protein interaction (PPI) network. Cytoscape was utilized to identify the top six hub genes.KEGG analysis was performed using DAVID. Expression validation of the hub genes and exploration of the correlation between hub genes expression and various other parameters was done through UALCAN, GEPIA, GENT2, cBioportal, TIMER, RegNetwork, and CTD. The six identified hub genes (GAL, GALR1, SST, SSTR2, NPY, and NPY1R) were enriched in diverse cancer-driving pathways. GAL was significantly up-regulated while other 5 hub genes (GALR1, SST, SSTR2, NPY, and NPY1R) were significantly down-regulated in colon adenocarcinoma (COAD) patients relative to controls.All these hub genes were hypermethylated and 5 out of 6 hub genes were found to be associated with the worst Overall survival (OS) of the COAD patients relative to control group. Furthermore, we explored some interesting associations between hub genes' expression and different other parameters including copy number variations (CNVs), CD+T immune cells infiltration, different other cancer states and crucial mutant genes across COAD samples. In addition, a few miRNAs (miR-27a-3p and miR-130a-3p) and drugs (triclosan, soman, reserpine, and isoproterenol, etc.) were found capable to alter the expression of hub genes and thus need to further be evaluated for their potential role in CRC treatment.In conclusion, the identified hub genes may provide new insight into the CRC biology and treatment.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.