The myeloid differentiation factor 88 (MyD88), an adaptor protein in regulation of the innate immunity, functions to regulate immune responses against viral and bacterial infections in the human body. Toll-like receptors (TLRs) and interleukin 1 receptors (IL-1R) can recognize microbes or endogenous ligands and then recruit MyD88 to activate the MyD88-dependent pathway, while MyD88 mutation associated with lymphoma development and altered MyD88 signaling also involved in cancer-associated cell intrinsic and extrinsic inflammation progression and carcinogenesis. Detection of MyD88 expression was to predict prognosis of various human cancers, e.g., lymphoid, liver, and colorectal cancers. In human cancers, MyD88 protein acts as a bridge between the inflammatory signaling from the TLR/IL-1R and Ras oncogenic signaling pathway. However, the MyD88 signaling played dual functional roles in colorectal cancer, i.e., the tumor-promoting role that enhances cancer inflammation and intestinal flora imbalance to induce tumor invasion and tumor cell self-renewal, and the anti-tumor role that helps to maintain the host-microbiota homeostasis to induce tumor cell cycle arrest and immune responses against cancer cells. This review precisely discusses the up to date literature for these contrasting effects of MyD88 signaling on colorectal cancer development and progression.