Paeoniflorin, a bioactive monoterpene glycoside derived from Paeonia lactiflora, has shown neuroprotective effects primarily associated with the promotion of brain-derived neurotrophic factor secretion. This study aims to elucidate the therapeutic potential of paeoniflorin in models of Parkinson’s disease and to investigate the role of the BDNF-mediated PI3K/Akt and ERK1/2/p90RSK/CREB signaling pathways. Notably, paeoniflorin improved motor function, grip strength, and partially restored tyrosine hy-droxylase -positive neurons in PD mice by regulating dopamine catabolism and inhibit-ing turnover, indicating dopaminergic protection. In vitro, paeoniflorin pretreatment enhanced cell viability, reduced LDH release, suppressed ROS and intracellular Ca²⁺ overload, stabilized mitochondrial membrane potential, and attenuated MPP⁺-induced apoptosis. A key innovation is the dual activation and synergistic interplay of the two BDNF-dependent pathways: LY294002 abolished paeoniflorin-induced BDNF/PI3K/Akt activation, while PD98059 and ERK1/2 siRNA specifically suppressed paeoniflor-in-triggered phosphorylation of ERK1/2, p90RSK, and CREB. Ultimately, paeoniflorin exerts robust neuroprotection against MPTP/MPP⁺ neurotoxicity by synergistically acti-vating BDNF-downstream PI3K/Akt and ERK/CREB axes. This delineation of a du-al-pathway mechanism provides novel insight into the pharmacological action of pae-oniflorin and supports its potential as a multifaceted therapeutic agent for Parkinson’s disease.