Cathepsin like 2 (CTSL2) is a lysosomal cysteine protease, and may be associated with tumor metastasis. However, CTSL2 has not been reported as a biomarker in lung adenocarcinoma (LUAD). In this study, bioinformatics analysis using data from The Cancer Genome Atlas was performed. Wilcoxon rank-sum test and chi-square test were carried out. Kaplan-Meier and Cox regression were performed to evaluate the effect of CTSL2 expression in the overall survival. Our results indicated that CTSL2 in tumor was significantly higher than that in normal tissue (P < 0.001). High CTSL2 expression was significantly associated with age (P = 0.02), vital status (P < 0.001), and T classification (P = 0.03), and correlated with poor overall survival (HR = 1.62, 95% CI = 1.21–2.18, P = 0.001). CTSL2 expression was an independent risk factor for overall survival in patients with LUAD (HR = 1.52, 95% CI = 1.12–2.05, P = 0.006). A nomogram was plotted for illustration of CTSL2 expression on the risk of LUAD. Furthermore, in vitro cell experiments showed the CTSL2 promoted the proliferation and migration of A549 cells. In summary, high CTSL2 expression predicts poor prognosis in patients with LUAD.