In vitro and in vivo models of Parkinson’s disease were established to investigate the effects of the lncRNA XIST/miR-199a-3p/Sp1/LRRK2 axis. The binding between XIST and miR-199a-3p as well as miR-199a-3p and Sp1 were examined by luciferase reporter assay and confirmed by RNA immunoprecipitation analysis. Following the Parkinson’s disease animal behavioural assessment by suspension and swim tests, the brain tissue injuries were evaluated by hematoxylin and eosin, TdT-mediated dUTP-biotin nick end labelling, and tyrosine hydroxylase stainings. The results indicated that miR-199a-3p expression was downregulated, whereas that of XIST, Sp1 and LRRK2 were upregulated in Parkinson’s disease. Moreover, miR-199a-3p overexpression or XIST knockdown inhibited the cell apoptosis induced by MPP+ treatment and promoted cell proliferation. The neurodegenerative defects were significantly recovered by treating the cells with shXIST or shSp1, whereas miR-199a-3p inhibition or Sp1 and LRRK2 overexpression abrogated these beneficial effects. Furthermore, the results of our in vivo experiments confirmed the neuroprotective effects of shXIST and miR-199a-3p against MPTP-induced brain injuries, and the Parkinson’s disease behavioural symptoms were effectively alleviated upon shXIST or miR-199a-3p treatment. In summary, the results of the present study showed that lncRNA XIST sponges miR-199a-3p to modulate Sp1 expression and further accelerates Parkinson’s disease progression by targeting LRRK2.