Parkinson's disease (PD) is an aging-associated neurodegenerative disease with a characteristic feature of alpha-synuclein accumulation. Point mutations (A53T, A30P) that increase the aggregation propensity of alpha-synuclein result in familial early onset PD. The abnormal metabolism of alpha-synuclein results in aberrant level changes of alpha-synuclein in PD. In pathological conditions, alpha-synuclein is degraded mainly by the autophagy-lysosome pathway. Triptolide (T10) is a monomeric compound isolated from a traditional Chinese herb. Our group demonstrated for the first time that T10 possesses potent neuroprotective properties both in vitro and in vivo PD models. In the present study, we reported T10 as a potent autophagy inducer in neuronal cells, which helped to promote the clearance of various forms of alpha-synuclein in neuronal cells. We transfected neuronal cells with A53T mutant (A53T) or wild-type (WT) alpha-synuclein plasmids and found T10 attenuated the cytotoxicity induced by pathogenic A53T alpha-synuclein overexpression. We observed that T10 significantly reduced both A53T and WT alpha-synuclein level in neuronal cell line, as well as in primary cultured cortical neurons. Excluding the changes of syntheses, secretion, and aggregation of alpha-synuclein, we further added autophagy inhibitor or proteasome inhibitor with T10, and we noticed that T10 promoted the clearance of alpha-synuclein mainly by the autophagic pathway. Lastly, we observed increased autophagy marker LC3-II expression and autophagosomes by GFP-LC3-II accumulation and ultrastructural characterization. However, the lysosome activity and cell viability were not modulated by T10. Our study revealed that T10 could induce autophagy and promote the clearance of both WT and A53T alpha-synuclein in neurons. These results provide evidence of T10 as a promising mean to treat PD and other neurodegenerative diseases by reducing pathogenic proteins in neurons.