Epidemiological studies have suggested that dietary fiber, especially from cereal sources, protects against colorectal cancer (CRC). The AICR/WCRF Second Expert Report upgraded the evidence for an inverse association between dietary fiber intake and CRC risk from “probably” to “convincing”. Although most studies show a correlation between whole grain (WG) consumption and reduction of the risk of CRC, the active components in WGs have not been fully explored. Most of the mechanisms proposed are based on the physiological function of fiber. Short-chain fatty acids especially butyrate, which are the fermentation products of wheat bran (WB) fiber by gut microbiota in the colon, have been proposed to be protective agents. Our recent studies have found that lipid-soluble phytochemicals, especially alkylresorcinols (ARs) are the active components in WB for colon cancer prevention. From a whole food viewpoint, it is critical to understand the interaction between different bioactive food components. Therefore, we studied whether sodium butyrate (NaB), the microbial derived metabolite of WB fiber, and ARs, the bioactive phytochemicals in WB, have additive/synergistic effects against the growth of human colon cancer cells. Our results indicated that NaB and AR C21 had synergistic effects against the growth of human colon cancer cells (HCT-116 and HT-29). Further mechanistic studies found that the levels of apoptosis were higher in combinations than in the individual compounds via activating the mitochondrial apoptotic pathway.