Objective: To study the regulatory effect of cryoablation on MAPK/ERK signaling pathway in mice with lung adenocarcinoma. Methods: Lewis mouse lung adenocarcinoma cell line was used to establish subcutaneous transplanted tumor model in C57BL / 6 mice. Ten mice were randomly divided into two groups: sham operation group and cryoablation group, with 5 mice in each group. The cryoablation group was treated with double circulation-rewarming ablation, and the sham operation group was treated with incision and suture at the transplanted tumor. The tumor tissues were taken 14 days after operation. Detect the effect of cryoablation on MAPK/ERK pathway related proteins by Western blot, such as KRAS, RAF1, MEK1, ERK1/2, P-RAF1, P-MEK1, P-ERK1/2. The expression of KRAS gene was further verified by qRt-PCR. Results: Compared with the sham operation group, the phosphorylated proteins P-RAF1, P-MEK1 and P-ERK1/2 in tumor tissue after cryoablation were decreased (P< 0.05 ), and the key molecule KRAS in MAPK/ERK pathway was decreased in protein and gene expression (P< 0.05 ). Conclusion: Cryoablation can negatively regulate MAPK / ERK signaling pathway by down-regulating KRas expression.