Long‐noncoding RNAs (lncRNAs) is involved in the development of diverse diseases, including leukemia, while the role lncRNA HOX transcript antisense RNA (HOTAIR) played in leukemia remains unclear and in need of further investigation. Therefore, this study was conducted to explore the effects of lncRNA HOTAIR on the immunologic rejection of leukemia cells through the Wnt/β‐catenin in mice. Mice were administrated with HOTAIR mimics as well as small interfering RNA HOTAIR to explore the regulatory role of HOTAIR. The numbers of white blood cell (WBC) and platelet (PLT) and the content of hemoglobin in peripheral blood (PB) were determined. The cytokine level in PB was measured. T‐lymphocyte proliferation activity, Ig production by B cells, natural killer (NK) cell activity, and the proportion of cluster of differentiation 4 (CD4)/CD8 T cell subsets were detected. Expression of HOTAIR, β‐catenin, cyclinD1, GSK‐3β, and c‐Myc in bone marrow was determined. It was revealed that the WBC number increased, while the PLT number along with the hemoglobin content in PB decreased with the upregulated HOTAIR. Additionally, elevated HOTAIR led to decreased levels of transforming growth factor‐β, interferon‐γ, interleukin‐10, and tumor necrosis factor‐α in PB, proliferation activity in T‐lymphocyte, and inhibited Ig production, NK cell activity, and the ratio of CD4/CD8 T cell subsets in B‐lymphocyte. Furthermore, Wnt/β‐catenin was activated by overexpressing HOTAIR. Enhanced survival and proliferation were shown with increased expression of cyclinD1, GSK‐3β, and c‐Myc in the bone marrow of mice induced by overexpressing HOTAIR. These results indicate that restored HOTAIR reduces the immunologic rejection of leukemia cells in mice by activating Wnt/β‐catenin pathway.