The present study aimed to explore the regulatory effects of endoplasmic reticulum stress (ERS) on the phosphoinositide 3‑kinase (PI3K)/AKT serine/threonine kinase 1 (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, and its subsequent effects on autophagy and apoptosis of human leukemia cells. Human leukemia cells were cultured and treated with various concentrations of tunicamycin for 0, 24, 48, 72 and 90 h. Subsequently, human leukemia cells were assigned into the ER activation group, which was treated with 100 ng/ml tunicamycin, the ER activation + TO901317 (PI3K inhibitor) group, and the control group. An MTT assay was conducted to detect cell proliferation. In addition, a monodansylcadaverine (MDC) assay was used to detect the formation of autophagosomes and Annexin V‑fluorescein isothiocyanate/propidium iodide double staining was used to examine cell apoptosis. Western blotting was performed to detect the expression levels of 78‑kDa glucose‑regulated protein (GRP78), phosphorylated (p)‑protein kinase R‑like endoplasmic reticulum kinase (PERK), p‑α subunit of eukaryotic initiation factor 2 (eIF2α), microtubule‑associated protein 1A/1B‑light chain 3 (LC3), caspase‑3, CCAAT‑enhancer‑binding protein homologous protein (CHOP), PI3K, AKT and mTOR. Treatment with 100 ng/ml tunicamycin for 72 h was considered the optimal condition for further experiments. Compared with in cells prior to treatment, human leukemia cells treated with tunicamycin exhibited increased expression of p‑PERK, p‑eIF2α and GRP78 after 72 h (P<0.05). In addition, the expression levels of mTOR, AKT and PI3K were decreased in the ER activation group compared with in the control and ER activation + TO901317 groups (P<0.05). Compared with in the control group, cell proliferation was inhibited and MDC fluorescence intensity was increased in the ER activation group (P<0.05). Furthermore, compared with in the control and ER activation + TO901317 groups, western blotting indicated that the expression levels of LC3‑II were increased in the ER activation group (P<0.05). The apoptotic rate was also higher in the ER activation group compared with in the control group (P<0.05), and caspase‑3 and CHOP expression was elevated in the ER activation group (P<0.05). These findings indicated that ERS may induce autophagy and apoptosis of human leukemia cells via inhibiting the PI3K/AKT/mTOR signaling pathway.