Alzheimer’s disease (AD) remains the most common neurodegenerative disease with amyloid beta (Aβ) formatted and accumulated. Recently, microRNAs have been identified as significant regulators in neurogenesis of the central nervous system (CNS). However, the biological role of miR-21 in AD remains unclear. The purpose of our study was to investigate the mechanism of miR-21 in AD. AD model was established using 20 μM Aβ_1–42 in SH-SY5Y cells. Aβ_1–42 can induce cell apoptosis via increasing Bax and decreasing Bcl-2 protein levels. Meanwhile, we observed that miR-21 was remarkably elevated by indicated Aβ_1–42 in vitro. Subsequently, miR-21 mimics were transfected into SH-SY5Y cells and it was found that miR-21 can inhibit cell apoptosis induced by Aβ_1–42. Programmed cell death protein 4 (PDCD4), an important tumor suppressor in various cancers has been reported to prevent AKT activation. The phosphatidylinositol 3-kinase (PI3K)/AKT/GSK-3β pathway can release a survival signal to protect from multiple injuries. Interestingly, it was found that PDCD4 was involved in miR-21-repressed cell apoptosis in AD models. miR-21 mimics can increase the PI3K, AKT and GSK-3β activity while PDCD4 ovexexpression inhibited their activity respectively. Moreover, knockdown of PDCD4 can rescue PI3K/AKT/GSK-3β pathway in SH-SY5Y cells. Taken these together, it was suggested by our data that miR-21 can exert protective roles in AD, which might be dependent on PDCD4/PI3K/AKT/GSK-3β signaling pathway in vitro.