Long noncoding RNAs (lncRNAs) have recently attracted increasing attention for their involvement in a wide variety of human neurodegenerative diseases, including Parkinson's disease (PD). The purpose of the present study was to investigate the functional role and underlying mechanism of NEAT1 in PD. qRT-PCR was used to assess the expression of NEAT1 and miR-221, and the expression levels of Bcl-2 and Bax were detected by western blot. Cell viability and apoptosis were determined by CCK-8 assay and flow cytometry, respectively. The changes of oxidative stress and neuroinflammation were evaluated by ELISA assay and qRT-PCR, respectively. The targeted interaction between NEAT1 and miR-221 was verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. Our data supported that MPP⁺ treatment elevated NEAT1 expression in dose- and time-dependent manners in SH-SY5Y cells, and NEAT1 silencing relieved MPP⁺-induced suppression of cell viability and enhancement of cell apoptosis in SH-SY5Y cells. Moreover, NEAT1 silencing alleviated MPP⁺-induced promotion of oxidative stress and neuroinflammation in SH-SY5Y cells. NEAT1 directly targeted miR-221 and negatively regulated miR-221 expression. More importantly, miR-221 mediated the protective effect of NEAT1 knockdown, as evidenced by the restoration of cell viability, cell apoptosis, oxidative stress and neuroinflammation in MPP⁺-induced SH-SY5Y cells. In conclusion, our study suggested that NEAT1 silencing alleviated MPP⁺-induced neuronal damage by sponging miR-221 in SH-SY5Y cells, highlighting the role of NEAT1 as a potential molecular target for PD therapy.