Growing evidence have shown the important regulation of lncRNAs (long noncoding RNAs) in non–small cell lung cancer (NSCLC). lncRNA hepatocyte nuclear factor 1 homeobox A (HNF1A)‐antisense RNA 1 (AS1), an “oncogene”, was reported to regulate human tumors progression. However, the molecular mechanism of HNF1A‐AS1 involved in the development of NSCLC is still under investigation. In the current study, we found that HNF1A‐AS1 was relatively upregulated in both NSCLC patient tissues and cell lines. Functional studies established that overexpression of HNF1A‐AS1 promoted cell proliferation, cell cycle, invasion, and migration of NSCLC cells in vitro. The promotion abilities of HNF1A‐AS1 on NSCLC cell progression were suppressed via knockdown of HNF1A‐AS1. miR‐149‐5p was then proved to be a novel target of HNF1A‐AS1, whose expression was negatively correlated with HNF1A‐AS1 in NSCLC patient tissues and cell lines. HNF1A‐AS1 increased the expression of cyclin‐dependent kinase 6 (Cdk6) via sponging with miR‐149‐5p. Gain‐ and loss‐of‐functional studies indicated that HNF1A‐AS1 promoted NSCLC progression partially through inhibition of miR‐363‐3p and induction of Cdk6. Subcutaneous xenotransplanted tumor model confirmed that interference of HNF1A‐AS1 suppressed the tumorigenic ability of NSCLC via upregulation of miR‐149‐5p and downregulation of Cdk6 in vivo. In conclusion, our findings clarified the biologic significance of the HNF1A‐AS1/miR‐149‐5p/Cdk6 axis in NSCLC progression and provided novel evidence that HNF1A‐AS1 may be a new potential therapeutic target for the treatment of NSCLC.