This article aims to study tripartite motif-containing protein 3 (TRIM3) effects on Parkinson's disease (PD). TRIM3 expression in venous blood of PD patients was detected by qRT-PCR. PD mouse model and PD SH-SY5Y cell model were constructed. PD cells were treated by LY294002 (a PI3K inhibitor). The apoptosis of PD mouse midbrain was detected. Glutathione (GSH) and superoxide dismutase (SOD) level in PD cells and mice midbrain was analyzed. Intracellular reactive oxygen species (ROS) and MMP were detected. The effect of TRIM3 on cell viability, apoptosis and PI3K/AKT signal pathway were analyzed. As a result, TRIM3 expression in venous blood of PD patients was decreased. TRIM3 up-regulation in PD mouse decreased midbrain tissues apoptosis. TRIM3 up-regulation increased GSH and SOD levels in PD mice midbrain tissues and PD cells. TRIM3 up-regulation in PD cells prominently reduced ROS and MMP. TRIM3 up-regulation increased PD cells viability and decreased apoptosis. TRIM3 up-regulation in PD cells elevated Bcl-2 protein expression and weakened Bax, Cleaved-caspase 3 and Cleaved-caspase 9 proteins expression. TRIM3 up-regulation increased p-PI3K/PI3K and p-AKT/AKT ratio. PI3K inhibitor treatment reversed the inhibitory effect of TRIM3 up-regulation on PD cells apoptosis. Thus, TRIM3 might attenuate apoptosis in PD via activating PI3K/AKT signal pathway.