Aim: Colorectal cancer (CRC) has developed into the third leading reason of cancer-associated death worldwide. Studies has confirmed that circular RNAs (circRNAs) sponge microRNAs (miRNAs) to regulate the function of downstream genes. This study aimed to expound the underlying mechanism of circRNA 100146 in CRC. Methods: The expression of circRNA 100146, miR-149 and high mobility group A2 (HMGA2) was detected by quantitative real time PCR (RT-qPCR). A series of bio-functional effects (cell viability, apoptosis, migration/invasion) were evaluated by methyl thiazolyl tetrazolium (MTT), flow cytometry, transwell. Protein level was measured by Western blot assay. The xenograft model was established for in vivo experiments. The interactions among circRNA 100146, miR-149 and HMGA2 were evaluated by dual-luciferase reporter assay, RNA immunoprecipitation assays, or RNA pulldown assay. Results: CircRNA 100146 was upregulated in CRC tissues and cells. CircRNA 100146 knockdown inhibited cell proliferation, promoted apoptosis and suppressed migration and invasion in vitro, and impeded tumor growth in vivo. Also, miR-149 was negalitively regulated by circRNA 100146, and targeted to HMGA2 and mediated its expression. Moreover, miR-149 interference abrogated the activities of silenced circRNA 100146 in proliferation, apoptosis, migration and invasion. Furthermore, HMGA2 overexpression abated the effects above caused by circRNA 100146 silencing, while the mutant on miR-149 binding sites in HMGA2 3’UTR lead to it losing this ability. Conclusion: CircRNA 100146 knockdown repressed proliferation, enhanced apoptosis and hindered migration and invasion in SW620 and SW480 cells through targeting miR-149/HMGA2 axis.