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Background. The acidic characteristics of the tumor microenvironment (TME) are attributed to cancer cells' needs of metabolism which produce a large amount of H+. In order not to affect its own life activities, it needs to release H+ into the intercellular space through an efficient Na+/H+ exchanger. On account of the intestine whose physiological function is highly dependent on intestinal pH value, NHE family members may play a critical role in the occurrence and development of colorectal cancer (CRC). Methods. TCGA, GEPIA2, ONCOMINE, UALCAN, STRING, TIMER, Cytoscape, TargetScan, ENCORI, LncBase v.2, DNMIVD, HPA, and CellMinerTM databases were used in our study. Results. The mRNA expressions of SLC9A1, SLC9A2, SLC9A3, and SLC9A9 were evidently lower in COAD than in normal samples; however, the mRNA expressions of SLC9A5, SLC9A8, and SLC9B2 were higher. Besides, mRNA expressions of NHE family were extremely associated with clinicopathological features, tumor immune microenvironment and stemness score, DNA methylation, and patient prognosis in COAD. Moreover, we conjectured that NHE family may play a role through MAPK or ErbB signaling pathway according to the results of GO/KEGG enrichment analysis. At last, we found that NHE family members were key factors of various kinds of cancers. Conclusion. Our study indicated that NHE family represented new diagnostic and therapeutic targets for CRC, which could have important significance for the clinical treatment of CRC. [ABSTRACT FROM AUTHOR]