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Background Growing evidence has implicated the important role of the long non-coding RNAs (lncRNAs) in gastric cancer progression. In this study, we examined the expression of lncRNA zinc finger E-box-binding homeobox 2 antisense RNA 1 (ZEB2-AS1) in gastric cancer tissues and elucidated the molecular mechanisms underlying ZEB2-AS1-mediated gastric cancer progression. Methods Quantitative real-time PCR measured the gene expression level; CCK-8, colony formation and cell invasion assays determined gastric cancer cell proliferation, growth and invasion, respectively; the xenograft nude mice model was used to determine in vivo tumor growth; Bioinformatics analysis and luciferase reporter assay determined the downstream targets of ZEB2-AS1 and miR-143-5p. The expression of ZEB2-AS1 was upregulated in gastric cancer cell lines. Results Knockdown of ZEB2-AS1 suppressed gastric cancer cell proliferation, growth and invasion, and also suppressed in vivo tumor growth in the nude mice. Overexpression of ZEB2-AS1 potentiated gastric cancer cell proliferation, growth and invasion. Bioinformatics analysis and luciferase reporter assay showed that miR-143-5p was a direct target of ZEB2-AS1 and was negatively regulated by ZEB2-AS1. Furthermore, hypoxia-inducible factor-1α (HIF-1α) was found to be a target of miR-143-5p and was negatively regulated by miR-143-5p. The rescue in vitro assays showed that the effects of ZEB2-AS1 overexpression on gastric cancer cell proliferation, growth and invasion was mediated via miR-143-5p/HIF-1α. ZEB2-AS1 and HIF-1α was upregulated in gastric cancer tissues, while miR-143-5p was down-regulated; and ZEB2-AS1 expression level was inversely correlated with miR-143-5p expression level, and positively correlated with HIF-1α mRNA expression level; while miR-143-5p expression level was inversely correlated with HIF-1α expression level. High ZEB2-AS1 expression level was correlated with poor differentiation, lymph node metastasis and distant metastasis. Conclusion Collectively, our results indicated that ZEB2-AS1 was up-regulated in gastric cancer tissues and cells and promoted cell proliferation and metastasis through miR-143-5p/HIF-1α pathway, which may provide a promising target for treatment of gastric cancer.