The pathogenesis of Parkinson's disease (PD) remains elusive. There is still no available disease-modifying strategy against PD, whose management is mainly symptomatic. A growing amount of preclinical evidence shows that a complex interplay between autophagy dysregulation, mitochondrial impairment, endoplasmic reticulum stress, oxidative stress, and excessive neuroinflammation underlies PD pathogenesis. Identifying key molecules linking these pathological cellular processes may substantially aid in our deeper understanding of PD pathophysiology and the development of novel effective therapeutic approaches. Emerging preclinical evidence indicates that apelin, an endogenous neuropeptide acting as a ligand of the orphan G protein-coupled receptor APJ, may play a key neuroprotective role in PD pathogenesis, via inhibition of apoptosis and dopaminergic neuronal loss, autophagy enhancement, antioxidant effects, endoplasmic reticulum stress suppression, as well as prevention of synaptic dysregulation in the striatum, excessive neuroinflammation, and glutamate-induced excitotoxicity. Underlying signaling pathways involve phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin, extracellular signal-regulated kinase 1/2, and inositol requiring kinase 1α/XBP1/C/EBP homologous protein. Herein, we discuss the role of apelin/APJ axis and associated molecular mechanisms on the pathogenesis of PD in vitro and in vivo and provide evidence for its challenging therapeutic potential.