The spleen is a secondary lymphoid organ that embraces several immune cells. It possesses an anti-tumor impact where splenectomies correlated directly to a significant increase of malignant tumor induction. The unmutant p53 and K-ras genes are expressed at low levels and play an essential role in the apoptosis of corrupted cells. We studied the impacts of p53 and K-ras transcriptions in some innated mediators' expressions on the spleen of mice bearing colon cancer. A number of Swiss mice were categorized into the untreated negative control group, and mice were injected with Azoxymethane carcinogen for colon cancer induction (AOM group). Both groups were subjected to TLR1, TLR2, IL1b, TNFa, IFNg, p53, and K-ras expression levels estimations after 4, 8, and 10 weeks from colon cancer induction. A significant increase in the p53 transcription level was observed at week 10, whilst K-ras transcription level upregulated significantly only at week 8 in the AOM group compared to the untreated group. The AOM spleen cells showed a late (weeks 8 and 10) significant upregulation and transcriptions on TLR1, TLR2, TNFa, and IFNg, levels, however, the IL1b transcription showed an early significant downregulation in comparison to those of the untreated group. Moreover, p53 transcription showed a significant correlation with TLR1 and TLR2 expressions, while K-ras transcription showed a significant correlation to the IL1b, TNFa, and IFNg, transcriptions levels. The study gave an insight into the confirmed correlation of p53 and K-ras transcriptions of mice spleen to some innate mediators during the induction of colon cancer.