BACKGROUND: Schisandrin B (Sch B) is an active component in Schisandra chinensis exerting anti-cancer effect, but the mechanism is obscure. This study was designed to explore the mechanism of Sch B against colorectal cancer (CRC). METHOD: Apparent experiments including cell proliferation, transwell, colony formation, etc. were carried out to assess the anti-cancer effect of Sch B to CRC cell lines, and the RNA-seq was performed prior to bioinformatics analysis to explore the key transcriptome alterations, furthermore, an untargeted metabolomics was carried out to profile the metabolic alterations after the treatment with Sch B and an integrated analysis and experiment validation were completed based on RNA-seq and metabolomics to find the critical mechanism. RESULT: The Sch B showed obviously inhibitory effect to cell proliferation, invasion and migration of CRC cell lines with a IC CONCLUSION: Sch B showed obviously anti-cancer effect to the CRC through inhibiting CXCL2/ERK/DUSP11 axis, but more experiments are needed to figure out the target of Sch B and validate this mechanism in vivo.