Objective:To investigate the signal pathway through which JMJD2B affected the malignant phenotype of human colorectal cancer cells. Methods: Human colorectal cancer cell lines HCT116 and SW1480 were interfered with siRNAs for silencing JMJD2B expression. The expression of ERK-MAPK signal pathway was detected by Western blotting, and cell proliferation was determined by CCK-8 assay, while cell cycle distribution and apoptosis were assessed by flow cytometry. Results: JMJD2B siRNA effectively and specifically inhibited the expression of JMJDB, which decreased ERK2 and its phosphorylation expression, and subsequently led to cell cycle arrest in G2/M or G0/G1 phase, increasing rates of cell apoptosis and significant cell proliferation inhibition (P < 0.05). Conclusion: Inhibition of histone demethylase JMJD2B restrained the malignant phenotype of human colorectal cancer cells via the inhibition of ERK-MAPK signal pathway transduction.