Parkinsonism is a common and disabling neurodegenerative disease. Drug-induced Parkinsonism is not uncommon. The neuroprotective actions of Piracetam and peroxisome proliferator-activated receptor gamma (PPAR γ) agonist pioglitazone have been reported. The aim of the current work was to investigate and compare the neuroprotective effect of piracetam versus pioglitazone on haloperidol-induced Parkinsonism. 36 male rats constituted the animal model for our study and had been divided into 6 groups (6 rats/group); control, Haloperidol, Piracetam, Piracetam with haloperidol, Pioglitazone, and Pioglitazone with Haloperidol groups. Hypokinesia was tested by stepping test and blood samples were collected for measurement of serum glucose, calcium, Creatine phosphokinase (CPK), Transforming growth factor beta 1 (TGF-β1), Fibroblast growth factor 21(FGF-21), Glial cell-Derived Neurotrophic factor (GDNF). Brains extracted for measurement of basal ganglia Tyrosin hydroxylase (TH) and Beclin gene expression. Haloperidol caused hypokinesia, increased serum glucose, CPK, TGF-β1, FGF-21, GDNF, basal ganglia TH expression and decreased serum calcium and basal ganglia Beclin expression. Both piracetam and pioglitazone provided neuroprotection and improved hypokinesia and the biochemical markers measured in blood and brains of haloperidol-induced Parkinsonism when administered before haloperidol, however; Pioglitazone had a better effect regarding the improvement of serum glucose, CPK and brain expression of Beclin.