Background: Parkinson's disease (PD), a prevalent and progressive neurodegenerative disorder, currently lacks effective and satisfactory pharmacological treatments. Computational drug repurposing represents a promising and efficient strategy for drug discovery, aiming to identify new therapeutic indications for existing pharmaceuticals. Methods: We employed a drug-target network approach to computationally repurpose FDA-approved drugs from databases such as DrugBank. A literature review was conducted to select candidates not previously reported as pharmacoprotective against PD. Subsequent in vitro evaluation utilized Cell Counting Kit-8 (CCK8) assays to assess the neuroprotective effects of the selected compounds in the SH-SY5Y cell model of Parkinson's disease induced by 1-methyl-4-phenylpyridinium (MPP+). Furthermore, an in vivo mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was developed to investigate the mechanisms of action and therapeutic potential of the identified drug candidates. Results: Our approach identified 176 drug candidates, with 28 selected for their potential anti-Parkinsonian effects and lack of prior PD-related reporting. CCK8 assays showed significant neuroprotection in SH-SY5Y cells for Omaveloxolone and Cyproheptadine. In the MPTP-induced mouse model, Cyproheptadine inhibited interleukin-6 (IL-6) expression and prevented Tyrosine Hydroxylase (TH) downregulation via the MAPK/NFκB pathway, while Omaveloxolone alleviated TH downregulation, potentially through the Kelch-like ECH-associated protein 1 (KEAP1)-NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. Both drugs preserved dopaminergic neurons and improved neurological deficits in the PD model. Conclusion: This study elucidates potential drug candidates for the treatment of Parkinson's disease through the application of computational repurposing, thereby underscoring its efficacy as a drug discovery strategy.