MicroRNAs (miRNAs) have been demonstrated to regulate the progression of numerous types of cancer, including acute myeloid leukemia (AML). Previous studies demonstrated that miR‑1271‑5p functions as a tumor suppressor; however, the roles of miR‑1271‑5p in AML remain unknown. In the present study, miR‑1271‑5p was significantly downregulated in AML tissues compared with normal tissues by reverse transcription‑quantitative polymerase chain reaction analysis. Furthermore, the expression levels of miR‑1271‑5p in patients with AML may function as a prognostic marker. In addition, overexpression of miR‑1271‑5p significantly suppressed the proliferation and induced apoptosis of AML cells by Cell Counting kit‑8 and fluorescence activated cell sorter assays; miR‑1271‑5p downregulation exhibited opposing effects. Additionally, transcription factor ZIC2 may be a direct target of miR‑1271‑5p in AML cells, which was demonstrated by a luciferase reporter assay and RNA pulldown assay. Overexpression of miR‑1271‑5p significantly reduced the mRNA and protein expression levels of ZIC2 in AML193 and OCI‑AML2 cells by reverse transcription‑quantitative polymerase chain reaction analysis and western blotting. Furthermore, an inverse correlation between miR‑1271‑5p and ZIC2 expression in AML samples was observed. In summary, ZIC2 was upregulated in AML tissues, and restoration of ZIC2 expression was able to promote the proliferation and reduce the apoptosis of AML cells transfected with miR‑1271‑5p mimics. The results of the present study demonstrated that miR‑1271‑5p inhibited the progression of AML by targeting ZIC2.