Objective To construct and verify a genetically engineered mouse model which is similar to clinical sporadic colorectal cancer and simultaneously expresses KrasLSL-G12D/- and Smad4loxp/loxp genes. Methods The Krastm4Tyj/J mouse and Smad4tm2.1Cxd/J mouse were transformed into the genetic background, and the genotypes of the offspring mice were identified by the PCR to obtain the mice expressed simultaneously KrasLSL-G12D/- and Smad4loxp/loxp genes. The LentivirusCre-IRES-Luciferase was injected into the submucosa of the model mice and the tumorigenicity was observed under the IVIS system. The tumor tissues of the model mice were sampled and the HE staining was used to verify the tumorigenicity of the model mice. Results The genetically engineered mouse model which could simultaneously express KrasLSL-G12D/- and Smad4loxp/loxp genes was obtained by the breeding and selection. The mouse intestinal epithelial cell carcinogenesis was successfully induced by the viral vector containing Cre recombinase. Conclusion Mouse model expressed simultaneously KrasLSL-G12D/- and Smad4loxp/loxp genes is capable of sporadic tumorigenicity by Cre recombinase and could simulate pathological process of human sporadic colorectal cancer.