The medicinal mushroom Ganoderma lucidum (G. lucidum) has been reported to possess a variety of pharmacological activities including anticancer effects. However, the anti-colorectal cancer effects and the potential molecular mechanisms of the ethanol extracts of sporoderm-broken spores of G. lucidum (BSGLEE), which mainly contains triterpenoids, have not been reported. The aim of the present study was to investigate the anticancer effects and molecular mechanisms exerted by BSGLEE on colorectal cancer in vitro and in vivo. MTT assay revealed that BSGLEE at 1.6 to 10 mg/ml significantly inhibited HCT116 cell proliferation in a dose- and time-dependent manner. Flow cytometric analysis demonstrated that BSGLEE induces apoptosis and cell cycle arrest at G0/G1 phase, which are associated with deregulation of the expression of key genes and proteins (p21, p16, cyclin D1, Bcl-2, bax, NAG-1, PARP and caspase-3) that regulate apoptosis and cell cycle cascades. Moreover, BSGLEE significantly inhibited HCT116 cell migration via downregulating MMP-1, MMP-2 and upregulating E-cadherin expression at mRNA levels. Oral gavage of 75 and 150 mg/kg BSGLEE significantly inhibited HCT116 xenograft tumor growth in nude mice, which was accompanied by suppressed Ki-67 staining as determined by immunochemistry. Collectively, we found that BSGLEE effectively inhibits colorectal cancer carcinogenesis through induction of apoptosis, inhibition of migration and promotion of cell cycle arrest. Our results suggest that triterpenoids of sporoderm-broken spores of G. lucidum ethanol extracts may serve as a promising anticancer agent for colorectal cancer chemoprevention and therapy.