To observe the effects of Jumonji C domain-containing (JMJD) 5 depletion on colon cancer (CC). A short-hairpin RNA targeting JMJD5 was transfected into a lentivirus to make Lv-shJMJD5 for infection into the Caco-2 human cell. Besides, a negative control shRNA was constructed. The mRNA and protein levels of JMJD5 were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Cell proliferation, migration, and invasion were assessed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), soft agar colony assay and transwell assay, respectively. In addition, immunohistochemical (IHC) staining was performed to investigate the expression of JMJD5 in adjacent normal tissues and tumor tissues from patients with CC. Compared with control group, mRNA and protein levels of JMJD5 was significantly reduced after infection with Lv-shJMJD5 (P< 0.05), and Caco-2 cell proliferation, migration, and invasion were all obviously inhibited (P< 0.05). The results of IHC showed that JMJD5 was significantly up-regulated compared with normal tissues (P< 0.01). Additionally, follow-up data demonstrated that the survival rate of patients with high expression of JMJD5 was obviously lower than that with low expression (P< 0.01). JMJD5 depletion could significantly inhibit human CC cell proliferation, migration, and invasion, implying that JMJD5 might be a potential oncogene.