AbstractBruceine D (BD) from Brucea javanica (L) exerts an antitumor effect in several human cancers. At present, it has not been reported whether BD inhibits the malignancy of colorectal cancer (CRC) cells. Therefore, investigating the role and regulatory mechanisms of BD in CRC is the main thrust of this study. Effect of BD on CRC cell viability, proliferation, apoptosis, invasion, and autophagy was determined by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide, 5‐ethynyl‐2′‐deoxyuridine, flow cytometry, transwell invasion, and western blotting assays. Expression changes of has_circ_0068464 (circ_0068464) were detected using real time quantitative polymerase chain reaction. The molecular mechanisms related to circ_0068464 were predicted through online prediction websites Starbase 2.0, circinteractome, and CircBank and validated using dual‐luciferase reporter and RNA pull‐down assays. The tumorigenic ability of BD and circ_0068464 on CRC was confirmed by xenograft experiments. The results showed that BD lessened CRC cell proliferation, invasion, autophagy, and prompted cell apoptosis. Circ_0068464 was overexpressed in CRC samples and cells. BD led to a significant reduction in circ_0068464 levels in cells of this carcinoma, but circ_0068464 overexpression partially rescued these effects urged by BD. Also, the combination of BD and circ_0068464 silencing decreased xenograft tumor growth compared to BD alone. Importantly, circ_0068464 could regulate ATG5 expression by functioning as a miR‐520h molecular sponge. In conclusion, BD might suppress CRC growth by inhibiting the circ_0068464/miR‐520h/ATG5 axis, providing a new perspective for the molecular pathogenesis of CRC and preliminarily indicating that BD may be a promising drug for CRC treatment.