Colorectal cancer (CRC) is the third leading cause of cancer deaths in the United States. A number of population studies have established that modifiable lifestyle factors such as obesity plays an important role in colorectal carcinogenesis. In the United States, more than one-third of adults are obese and obesity prevalence rates have no sign of decrease. Therefore, the development of effective strategies to prevent obesity-induced CRC is a public health priority. This study aimed to investigate whether genetic or dietary strategies can prevent obesity-induced CRC and determine the potential molecular mechanisms underlying the prevention effects of these strategies. We used Apc1638N mice, germline heterozygous mutation in the Apc gene, and Caco-2 cell line to study intestinal tumorigenesis. Hematoxylin and eosin stain and QuickPlex SQ 120, a chemiluminescence assay, were used to measure the inflammatory status. Real-time PCR, Western blot assay, and immunohistochemical analysis were used to further examine the signaling pathway status. We found that loss of Tumor necrosis factor alpha (TNF-α) decreased obesity associated intestinal tumorigenesis by decreasing the inflammation, and manipulating the β-catenin pathway and NF-kB signaling. In addition, IKK, a component of the NF-kB signaling, was involved in the regulation of β-catenin pathway. The administration of Vitamin D (VD), at 5000 IU level, exerted an anti-inflammatory property and led to suppressed intestinal Wnt-signaling and tumorigenesis in obese mice. The molecular function of sulforaphane (SFN) on a high dose of VD supplementation, although displayed on the inhibition of HDAC and the activation of autophagy, needs further investigation. Butyrate can increase the activity of Wnt/β-catenin pathway. Knocking down FFAR2 by siRNA decreased the expression of cleaved caspase 3 and the expression of phospho-GSK3β (Ser9) and active β-catenin in Caco-2 cells, subsequently mitigated the anticancer effect of butyrate.