Ginsenoside Rg1 (Rg1) has been shown to treat a variety of human diseases, including Alzheimer's disease (AD). However, its mechanism in AD needs further investigation. Microglial cells (BV2) were treated with Aβ to induce AD cell models. Cell viability and apoptosis were tested by cell counting kit 8 assay and flow cytometry. The protein levels of GATA-binding protein 4 (GATA4), phosphodiesterase 4A (PDE4A), autophagy-related markers, M1/M2 polarization-related markers and PI3K/AKT-related markers were detected by western blot. Inflammation factors were detected by ELISA. Jaspar and dual-luciferase reporter assay were used to evaluate the interaction between GATA4 and PDE4A. Our results showed that Rg1 promoted viability and autophagy, while suppressed apoptosis and inflammation in Aβ-induced BV2 cells. Rg1 reduced GATA4 protein expression, and GATA4 upregulation reversed the regulation of Rg1 on Aβ-induced BV2 cell injury. GATA4 interacted with PDE4A, and GATA4 facilitated Aβ-induced BV2 cell injury by increasing PDE4A expression. Besides, GATA4 knockdown reduced PDE4A protein expression and inactivated PI3K/AKT axis, while these effects were abolished by PDE4A overexpression. In conclusion, our data suggested that Ginsenoside Rg1 inhibited microglial cell apoptosis and inflammation to attenuate AD progression by regulating the GATA4/PDE4A/PI3K/AKT axis.