The aim of the current study was to examine the protective effects and mechanisms of Ndfipl on neurocytes in an experimental in vitro Parkinson's disease model induced by MPP+. The cell model was developed with dominant negative expression and suppressed expression of Ndfipl by means of transient transfection of Ndfipl-dominant negative and -inhibitory vectors. In total, four different Ndfipl cell models were established. Different methods were used to analyze the cells. The MTT method was used to detect the effect of Ndfipl on the survival rate and apoptosis of the cells induced by MPP(+). We further studied the roles of Ndfipl in inhibiting MPP(+)-induced SH-SY5Y apoptosis, protection, and ubiquitination of SH-SY5Y cells. Our results showed that Ndfipl reduced apoptosis and improved cell survival rate, indicating that Ndfipl has a neuroprotective effect. Furthermore, we found that Ndfipl binds to Nedd4-1, and that increased expression of Ndfipl significantly reduced Itch expression. We also found that increased ubiquitination played a role in Ndfipl-mediated processes, and that Ndfipl and α-synuclein interact. Additionally, the expression of Ndfipl reduced expression of α-synuclein. In conclusion, Ndfipl plays a significant role in protecting SH-SY5Y cells in in vitro Parkinson's disease models.