Mitochondrial dysfunction is widely considered one of the key initiating factors leading to Parkinson's disease (PD). Mitophagy plays a critical role in maintaining mitochondrial homeostasis. Complement C1q-binding protein (C1QBP) plays a crucial role in regulating mitophagy and maintaining mitochondrial homeostasis. This study aims to investigate the role of C1QBP in the pathogenesis of PD by employing bidirectional modulation of C1QBP expression in the PD models. Our results showed reduced C1QBP expression in PD models. C1QBP deficiency aggravated motor dysfunction and dopaminergic neuron degeneration induced by MPTP, while its overexpression exerts protective effects. Mechanistically, C1QBP ameliorates MPP+-induced mitochondrial dysfunction, thereby attenuating neuronal loss. Furthermore, C1QBP promotes mitophagy to maintain mitochondrial homeostasis in PD models. However, these neuroprotective effects of C1QBP were abolished upon UNC-51-Like Kinase 1 (ULK1) knockdown. Collectively, our study has identified C1QBP as a novel guardian for dopaminergic neurons in Parkinson's disease by targeting ULK1 to promote mitophagy and maintain mitochondrial function.