Parkinson's disease (PD) is an age-related progressive disorder that leads to dopaminergic loss and subsequent motor dysfunction. Current therapies mainly deal with symptomatic effects, and hence, therapies targeting progressive neurodegeneration need to developed. In this study, tirzepatide, a coagonist of glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, exhibited a neuroprotective effect in preliminary studies. This study aims to evaluate the effect of tirzepatide, in comparison with exendin-4, in a rat model of PD. The effect of tirzepatide (50 and 100 nmol/kg, s.c.) and exendin-4 (8 μg/kg, s.c.) on behavioral functions, oxidative markers, inflammatory markers, dopamine level, and alpha-synuclein expression were studied against a rotenone (2 mg/kg)-induced toxicity model in rats. Tirzepatide prevented rotenone-induced motor deficits. Additionally, it significantly inhibited the rotenone-induced increase in proinflammatory cytokines TNF-α and IL-6. Furthermore, it upregulated striatal dopamine levels. It alleviated oxidative stress and alpha-synuclein aggregation. Both doses of tirzepatide exert neuroprotective effects in a PD rat model. Furthermore, the effect is dose-dependent, and a 100 nmol/kg dose of tirzepatide was found to be more effective.