This study aimed to investigate and characterize Parkinson’s-like behavioral, histological, and biochemical changes induced by feeding fructose (10% w/v) for 24 weeks in rats. Additionally, we aimed to evaluate the potential protective effect of dulaglutide and empagliflozin either individually or combined with pirfenidone on fructose-induced Parkinsonian features. Rats were given 10% w/v fructose solution for 24 weeks and cotreated for the last 4 weeks with either empagliflozin (30 mg/kg/day orally), dulaglutide (0.2 mg/kg/week subcutaneously), pirfenidone (100 mg/kg/day orally), or the combination of the latter with empagliflozin or dulaglutide at the same mentioned doses. Behavioral testing was done at the end of the study period, and brain tissue samples were taken at sacrifice. Fructose-fed rats showed aberrations in cognitive function and motor coordination constellated with loss of substantia nigra neurons, dopamine deficiency, and altered α-synuclein, LRRK2, and parkin expression. This was associated with insulin resistance, dyslipidemia, enhanced neuroinflammation, and apoptosis. All treatments ameliorated these perturbations with more pronounced effects observed in the combination groups. Current results revealed the neuroprotective potential of dulaglutide, empagliflozin, and pirfenidone against fructose-induced neurobehavioral alterations in rats with an additive effect observed with the combined therapy.