Esophageal cancer is one of the most aggressive malignancies with poor prognosis. The administration of the first- and second-generation platinum drugs is frequently accompanied by drug resistance and severe toxicity. The aim of present study is to investigate the anti-tumor activity of the third-generation platinum drug Lobaplatin against esophageal squamous cell carcinoma in vitro and in vivo, and clarify the underlying molecular mechanism. The cytotoxicity of Lobaplatin against esophageal squamous cell carcinoma cell lines was determined by the MTT and clonogenic assay. Cell apoptosis was assessed by Annexin V-FITC/PI apoptosis assay using flow cytometry. The expression of proteins was determined by western blot analysis. The in vivo anti-tumor activity was evaluated in nude mice xenograft. Lobaplatin significantly inhibited the growth of KYSE-410 and EC-109 cells in a dose- and time-dependent manner and induced cell apoptosis by increasing expressions of cleaved-caspase-3, cleaved-caspase-8, cleaved-caspase-9 and Bax, decreasing expression of Bcl-2. In vivo study showed that Lobaplatin suppressed tumor growth of EC-109 xenograft. Lobaplatin significantly inhibited the growth of esophageal squamous cell carcinoma by inducing apoptosis through the caspase-dependent pathway. Lobaplatin is an effective anti-cancer agent against esophageal cancer.