Parkinson’s disease (PD) is characterized by dopaminergic neuron loss, motor dysfunction, and Lewy body formation. Src homology 2B adaptor protein 2 (SH2B2), a member of the SH2B family with known roles in neuroregulation, has not been fully explored in PD. This study aimed to investigate the neuroprotective effects and mechanisms of SH2B2 in PD. MPTP-induced mouse model and MPP+-treated SH-SY5Y cell model were established to simulate PD in vivo and in vitro. Mice were randomly divided into saline, MPTP, MPTP + OE-NC, and MPTP + OE-SH2B2 groups, while SH-SY5Y cells were randomly grouped into control, MPP+, MPP+ + OE-NC, and MPP+ + OE-SH2B2. Behavioral tests, Nissl staining, IHC, CCK-8, flow cytometry, qRT-PCR, and Western blot were used to assess outcomes. Our findings indicated that SH2B2 was downregulated in MPTP-induced mice and MPP+-treated SH-SY5Y cells (P < 0.01). Overexpressing SH2B2 improved motor function in mice (evidenced by the prolonged rotarod and wire hang latencies and shortened pole climbing time (P < 0.01)), upregulated TH expression (P < 0.001), downregulated IBA1 levels (P < 0.001), and alleviated dopaminergic neuron atrophy and Nissl body loss (P < 0.001). In SH-SY5Y cells, overexpressing SH2B2 reversed MPP+-induced cell viability reduction and apoptosis (P < 0.05). This study confirmed SH2B2 downregulation in PD models and demonstrated that overexpressing SH2B2 alleviates dopaminergic neuron injury and neuroinflammation, improving motor function. Therefore, SH2B2 emerges as a novel neuroprotective factor and potential therapeutic target for PD, warranting further research into its molecular mechanisms for clinical translation.