Objective To explore the effect of low expression of circular RNA homeodomain- interactingproteinkinases 3 (circHIPK3) on the apoptosis of hippocampal neurons induced by Amyloid β-protein (Aβ). Methods Bioinformatics software prediction and double luciferase reporter gene experiments were used to investigate the targeting relationships between microRNA-124 (miR-124) with HIPK3 and signal transduction and activator of transcription 3 (STAT3). Primary hippocampal neurons were cultured in vitro and divided into the control group (normal cultured), the amyloid β-protein ( Aβ) group ( Aβ stimulation), the Aβ + siSTAT3-NC group ( Aβ stimulation after transfection of siSTAT3-NC), the Aβ+siHIPK3 group (Aβ stimulation after transfection of siHIPK3), the Aβ+siHIPK3+antimiR-NC group (Aβ stimulation after cotransfection of siHIPK3 and inhibitor-NC), the Aβ + siHIPK3 + antimiR-124 group ( Aβ stimulation after cotransfection of siHIPK3 and miR-124 inhibitor), the Aβ+siHIPK3+antimiR-124+siSTAT3-NC group (Aβ stimulation after cotransfection of siHIPK3, miR-124 inhibitor and siSTAT3-NC) and the Aβ+siHIPK3+antimiR-124 +siSTAT3 group (Aβ stimulation after cotransfection of siHIPK3, miR-124 inhibitor and siSTAT3). The expression levels of HIPK3 and miR-124 were detected by real-time fluorescence quantitative PCR ( qRT-PCR), and expression level of STAT3 protein was detected by Western blot. Survival and apoptosis rates of hippocampal neurons were measured by the thiazole blue ( MTT) method and flow cytometry, respectively. Caspase-3 activity was detected by Cysteine-containing aspartate proteolytic enzyme 3 (Caspase-3) activity detection kit. Results Bioinformatics and double luciferase reporter gene experiments showed that HIPK3 targeted miR-124. Bioinformatics, double luciferase reporter gene experiments and Western blot demonstrated that miR-124 targeted STAT3 protein expression. Compared with the control group, expression levels of HIPK3 and STAT3 protein, and the apoptosis rate and caspase-3 activity in hippocampal neurons were significantly higher in the Aβ group, whereas the survival rate of neurons and expression level of miR-124 were significantly lower (P< 0. 05). Compared with those in the Aβ+siSTAT3-NC group, the above indexes were significantly reversed in the Aβ+ siHIPK3 group ( P< 0. 05). Compared with those in Aβ + siHIPK3 + antimiR-NC group, the above indexes showed significant changes in the Aβ+siHIPK3+antimiR-124 group (P< 0. 05), and the trend was opposite to those in the Aβ+ siHIPK3 group. Compared with the Aβ+siHIPK3 +antimiR-124 +siSTAT3-NC group, the indexes of the Aβ+siHIPK3 + antimiR-124+siSTAT3 group were markedly changed (P< 0. 05), and the trend was opposite to those of the Aβ+siHIPK3 +antimiR-124 group. There were no significant differences between the Aβ and Aβ+siHIPK3-NC groups, the Aβ+siHIPK3 and Aβ+siHIPK3+antimiR-NC groups, or the Aβ+siHIPK3+antimiR-124+siSTAT3-NC and Aβ+siHIPK3+antimiR-124+ siSTAT3 groups. Conclusions The low expression of circHIPK3 can inhibit apoptosis of hippocampal neurons induced by Aβ, and its mechanism is related to regulation of the miR-124 / STAT3 axis.