There is a strong belief that garlic has medicinal properties and may even reduce the risk of developing certain cancers including those of the gastrointestinal tract. The chemopreventive effects of garlic may be attributed to the anti-inflammatory properties of garlic’s sulfur-containing constituents, which includes diallyl disulfide (DADS). Here we demonstrate that DADS prevented colorectal tumorigenesis in a mouse model of colitis-induced colorectal cancer. Supplementation with 85ppm of DADS (60 mg daily human equivalent dose) in the diet of FVB/N mice treated with chemical carcinogen azoxymethane (AOM) and colonic irritant dextran sodium sulfate (DSS) resulted in the reduction in tumor incidence, tumor number and tumor burden by 21.54%, 47.3%, and 66.4%, respectively. Further analysis revealed that mice fed the DADS supplemented diet resolved the initial DSS-induced inflammation faster than those on the control diet, preventing prolonged inflammation and cellular transformation. Subsequent mechanistic studies in vitro suggest that DADS chemopreventive effects are mediated through NFκB signaling. When SW480 colorectal cancer cells were treated with DADS, NFκB nuclear localization and activity was diminished. Interestingly, NFκB suppression was found to be dependent on DADS inhibition of GSK-3β, a positive regulator of NFκB. Inhibition of GSK-3β and loss of nuclear NFκB activity were also observed in vivo in AOM/DSS treated mice fed a diet supplemented with 85ppm DADS. Our results indicate that DADS can prevent tumorigenesis by suppressing inflammation, a process largely involving GSK-3β inhibition and consequential reduction in NFκB nuclear localization.