Background Studies have shown that E3 ubiquitin ligase CBLL1 plays multiple roles in development and tumorigenesis. CBLL1 is over‐expressed in colon cancer and associated with cancer cell proliferation. While, the overexpression of CBLL1 inhibited the estrogenic dependent cell proliferation and migration in ER alpha dependent breast cancer cell MCF‐7. Methods We used an immunohistochemical method to detect CBLL1 expression in human NSCLC and corresponding normal lung tissues and analyzed its relationship with clinicopathological parameters. Moreover, we investigated the role of CBLL1 in NSCLC cell behavior by inhibiting its expression in A549 and H1299 cells. Results In this study, we found that CBLL1 was frequently upregulated in non‐small lung cancer (NSCLC) tissues compared to the adjacent nontumor tissues. We found that the high expression of CBLL1 was associated with the tumor size in NSCLC tissues. It has been recently reported that CBLL1 promotes cell proliferation and invasion in A549 and H460 cells. Our results confirmed that CBLL1 promoted the proliferation by promoting G1/S cell cycle transition in NSCLCs cells. Moreover, CBLL1 knockdown inhibited cell invasion via increased E‐cadherin protein expression, and decreased expression of MMP2 and MMP9 in NSCLC cell lines. The protein expression of E‐cadherin was increased after CBLL1 depletion while the E‐cadherin mRNA was not affected after knockdown of the endogenous CBLL1. Conclusion These results provide important insights for using CBLL1 as an oncogenic marker gene in the development and progression of non‐small cell lung cancer.