Abundant evidence indicates that long noncoding RNAs (lncRNAs) play an important role in various cellular processes, tumorigenesis, and the development of cancer. An increasing number studies are exploring this lncRNA-mediated mechanism. CASC2 is a novel gene in lncRNAs, located at chromosome 10q26. The present study aimed to examine the expression of lncRNA CASC2 in esophageal carcinoma (EC) tissue and to explore the effect of the upregulation of CASC2 on EC cell lines and specific regulatory mechanisms. We found the expression of CASC2 to be significantly downregulated in EC tissues and EC cell lines; moreover, low expression of CACS2 was associated with advanced TNM stage and lymph node metastases. Furthermore, upregulation of CASC2 significantly inhibited the proliferation of EC cells both in vitro and in vivo as well as their invasion in vitro; it also induced the apoptosis of EC9706 and EC1 cells. Additional experiments indicated that CASC2 interacted directly with miR-18a-5p, and there was a negative correlation between miR-18a-5p and CASC2 in EC tissues. We also found that miR-18a-5p directly targeted PTEN, a tumor suppressor gene, and could downregulate the protein expression of PTEN. Our experiments suggest that CASC2, acting as a competing endogenous RNAs (ceRNAs) of miR-18a-5p, exerts its biological effects by modulating the expression of PTEN. These findings indicate that the CASC2–miR-18a-5p–PTEN axis may be a novel target for further studies aimed at the prevention and treatment of EC.