Progesterone is often used to protect the endometrium and prevent endometrial cancer. An intensive study on its molecular mechanism in endometrial cancer would contribute to the development of more promising therapies. Relevant lncRNAs and mRNAs expression data in endometrial cancer cell line Ishikawa pretreated and post‐treated with progesterone were derived from Gene Expression Omnibus (accession no. GSE29435), and then we analyzed long noncoding RNAs and mRNAs with differential expressions in two different conditions. The Cytoscape software, TargetScan, miRanda, and Human microRNA Disease Database (HMDD) websites were employed. Gene set enrichment analysis (GSEA) was used to determine related Kyoto Encyclopedia of Genes and Genomes pathways alteration in Ishikawa cells treated with progesterone. In addition to bioinformatics analysis, Reverse Transcription‐Polymerase Chain Reaction (RT‐PCR), Western blot, and dual‐luciferase reporter assays were performed. The impact of progesterone on cell propagation and cell cycle was testified by colony formation and flow cytometry analysis. LncRNA nuclear enriched abundant transcript 1 (NEAT1) was the most significantly downregulated lncRNA in endometrial cancer cells treated with progesterone. Lymphoid enhancing factor 1 (LEF1) was positively associated with NEAT1, and eventually hsa_miR‐146b‐5p was validated to target both LEF1 and NEAT1. Wnt/β‐catenin signaling pathway was identified to involve in endometrial cancer. NEAT1 or LEF1 was overexpressed in endometrial cancer cells while downregulated following post‐treatment with progesterone. Conversely, miR‐146b‐5p was notably decreased in Ishikawa cells while upregulated after treatment with progesterone. Downstream gene c‐myc or MMP9 regulated by upstream gene LEF1 in Wnt/β‐catenin signaling pathway was remarkably increased in Ishikawa cells and positively related with NEAT1. Progesterone inhibited cell cycle and viability through regulating NEAT1/miR‐146b‐5p axis via Wnt/β‐catenin signaling pathway. Progesterone exerted suppressive influence on endometrial cancer progression via regulation of lncRNA NEAT1/miR‐146b‐5p‐mediated Wnt/β‐catenin signaling pathway, which might reveal new strategies for developing more effective therapeutics. © 2018 IUBMB Life, 71(1):223–234, 2019