Epidermal growth factor receptor (EGFR) is widely accepted in cancer diagnosis and targeted therapy. Shkbp1 is an upstream molecule of EGFR, which prevents EGFR degradation. However, the role of Shkbp1 in tumor remains to be clarified. Herein we induced tumor in the lungs of Shkbp1 knockout mice with chemical drugs to investigate the function of Shkbp1. Compared with wild-type mice, tumors in the lungs were significantly fewer in Shkbp1 knockout mice. To further explore the biological characteristics and functions of Shkbp1 in cancer cells, we established cell lines with overexpression and low expression of Shkbp1, respectively. Results from our experiments showed that low expression of Shkbp1 in lung cancer remarkably inhibited cancer cell migration and invasion, while overexpression of Shkbp1 promoted their migration and invasion, which indicated that Shkbp1 was closely related with tumor migration and invasion. The mRNA expression analysis of 494 matched tumor and adjacent non-tumor tissues (data derived from TCGA database) revealed that Shkbp1 was associated with the clinic TNM staging. Furthermore, immunohistochemistry (IHC) analysis of tissue microarrays showed that Shkbp1 was also correlated with lymphatic metastasis. Mechanistically, we observed that Shkbp1 was associated with epithelial-mesenchymal transition (EMT) marker. More interestingly, Shkbp1 was also expressed in a variety of immune cells, and we hereby used a subcutaneous transplantation tumor model and a metastasis model created by tail vein injection to explore whether Shkbp1 could impact tumor growth. The results showed that Shkbp1 knockout reduced tumor growth in both tumor models. In general, our results suggest that knocking out Shkbp1 in either immune cells or tumor cells could suppress tumor growth and metastasis.