As an important endogenous growth factor, PDGF-BB can effectively promote neurogenesis, thus is considered as a potential agent for Parkinson's disease (PD) therapy. However, the protective function of PDGF-BB on neuronal cells, especially the molecular mechanism, remains less clear, which is needed to explore before its clinical practice. In this study, we investigated the function and mechanism of PDGF-BB against 1-methyl-4-phenylpyridinium (MPP+) toxicity in SH-SY5Y cells, a widely used cellular tool for PD-related molecular study. Our results indicated that PDGF-BB exerts a prominent protective effect against neurotoxin MPP+-triggered ROS generation and cellular loss. We further dissected the molecular mechanism involved in this process by using specific pharmacological inhibitors and validated that the distinct signaling pathways PI3K/Akt/GSK-3 beta and MEK/ERK are involved in the process against MPP+ toxicity upon PDGF-BB treatment. We also detected that activation of upstream PI3K/Akt/GSK-3 beta and MER/ERK signaling pathways contribute to phosphorylation and nuclear translocation of the downstream effector cyclic response element-binding protein (CREB), a known transcription factor to exhibit neuroprotective and growth-promoting effects. Using genetic approach, we further confirmed that the activation of CREB is involved in PDGF-BB-mediated protection in MPP+-exposed SH-SY5Y cells. Together, these data demonstrated the protective effect of PDGF-BB in MPP+-mediated toxicity in SH-SY5Y cells and verified the involved molecular mechanism in PDGF-BB-mediated neuroprotection.