Background Colon cancer is the third most commonly diagnosed cancer with high morbidity and mortality. Calmodulin‐binding transcription activator 2 (CAMTA2) belongs to the calmodulin‐binding transcription activator protein family. The functional role of CAMTA2 in colon cancer development remains unclear. Our research found out that CAMTA2 was high‐level expressed in colon cancer, and the upregulated CAMTA2 expression was markedly correlated with poor survival. Functional experiments showed that knockdown of CAMTA2 repressed colon cancer cell proliferation/migration in vitro and attenuated proliferation in vivo. In additional, CAMTA2 expression was controlled by miR‐28‐5p via posttranscriptional regulation and miR‐28‐5p expression was reversely correlated with CAMTA2 expression in colon cancer. Moreover, enforced miR‐28‐5p expression downregulated the expression of CAMTA2 significantly and the restoration of CAMTA2 expression abolished the inhibitory effect of miR‐28‐5p on colon cancer cell proliferation and metastasis. Mechanistically, overexpression of miR‐28‐5p suppressed Wnt/β‐catenin signaling and the inhibitory could be partly abolished by overexpression of CAMTA2. In summary, our findings reveal that miR‐28‐5p/CAMTA2 axis plays a critical role in human colon cancer, which might be a promising diagnosis and therapeutic target for colon cancer treatment.