Parkinson's disease (PD) is an incurable progressive disorder resulting from neurodegeneration, and apoptosis is considered a dominant mechanism underlying the process of neurodegeneration. MicroRNAs (miRNAs), which are small and noncoding RNAs involved in many a biological process like apoptosis and regulation of gene expressions, have been found in postmortem brain samples of patients with PD, as well as and models of PD. To explore the impact of miR-15b-5p and Akt3 on apoptosis in the progression of PD, the method of quantitative reverse transcription polymerase chain reaction (qRT-PCR) was employed, and the analysis result showed upregulated expression of miR-15b-5p and downregulated expression of Akt3 in the serum of PD patients, MPP-induced SH-SY5Y cells, and the brain tissues of MPTP-induced mice. Meanwhile, the dual-luciferase reporter assay was used to demonstrate the regulator-target interaction between miR-15b-5p and Akt3; flow cytometry and spectrophotometry revealed that transfection of miR-15b-5p mimic and si-Akt3 increased the rate of apoptosis and caspase-3 activity, whereas transfecting the miR-15b-5p inhibitor and Akt3-overexpression plasmid repressed the rate of apoptosis and caspase-3 activity in the MPP-induced SH-SY5Y cell model and the MPTP-induced mouse model. Additionally, analysis of western blotting (WB) assays and revealed that proapoptosis proteins (Bax, caspase-3, GSK-3, and -catenin) showed markedly upregulated expression in the miR-15b-5p inhibitor and si-Akt3-overexpression groups, while the expression of an antiapoptosis gene (i.e., Bcl2) was downregulated. These analysis results indicate that downregulation of miR-15b-5p by targeting the Akt3-mediated GSK-3/-catenin signaling pathway would repress cell apoptosis in PD and . It is expected that the research findings would help find new therapeutic targets for treatment of PD.