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Forkhead box O1 (FOXO1) is a key regulator of osteogenesis. The aim of this study was to identify the mechanisms of microRNAs (miRNAs) targeting FOXO1 in osteogenic differentiation of human bone marrow mesenchymal stem cells (hMSCs). Three miRNA target prediction programs were used to search for potential miRNAs that target FOXO1. Quantitative real‐time polymerase chain reaction was conducted to detect the expression of miR‐1271‐5p and FOXO1 during osteogenic differentiation. Target gene prediction and screening, luciferase reporter assay was used to verify the downstream target gene of miR‐1271‐5p. The expression levels of FOXO1 and Runx2 were detected by RT‐qPCR and Western blot analysis. Alkaline phosphatase (ALP) activity and matrix mineralization were detected by biochemical methods. The expression levels of Runx2, ALP, and osteocalcin were detected by RT‐qPCR. Our results showed that miR‐1271‐5p was downregulated during osteogenic induction. And the expression levels of miR‐1271‐5p were higher in osteoporotic tissues than that in adjacent nonosteoporotic tissues. The expression levels of FOXO1 were lower in osteoporotic tissues than that in adjacent nonosteoporotic tissues. And a negative correlation was found between miR‐1271‐5p and FOXO1 in osteoporotic tissues. Overexpression of miR‐1271‐5p downregulated FOXO1 and inhibited osteogenic differentiation in hMSCs. Overexpression of miR‐1271‐5p downregulated the expression of osteogenic markers and reduced ALP activity. In addition, ectopic expression of FOXO1 reversed the effect of miR‐1271‐5p on osteogenic differentiation. In conclusion, miR‐1271‐5p functioned as a therapeutic target of osteogenic differentiation in hMSCs by inhibiting FOXO1, which provides valuable insights into the use of miR‐1271‐5p as a target in the treatment of osteoporosis and other bone metabolic diseases. [ABSTRACT FROM AUTHOR]