This study investigated the molecular mechanisms underlying the neuroprotective effects of vitamin E in a rotenone-induced Parkinson’s disease (PD) rat model, in comparison to levodopa/carbidopa (LD/CD), and evaluated the benefit of their combined use. PD was induced by rotenone (2.5 mg/kg/day, i.p) for 42 days. On day 14, disease onset was confirmed via behavioral deficits and reduced striatal tyrosine hydroxylase (TH) levels. From day 15 to day 42, Parkinsonian rats received vitamin E (100 IU/kg/day, i.p), LD/CD (20/5 mg/kg/day, i.p), or both. ROT-intoxicated rats exhibited progressive motor dysfunction, striatal neurodegeneration, neuronal loss, reduced TH/dopamine levels, and α-synuclein aggregation. These changes were associated with suppressed AMPK/SIRT1/PGC-1α signaling, impaired mitochondrial biogenesis and function, defective mitophagy, heightened oxidative stress, and upregulation of the pro-inflammatory HMGB1/RAGE pathway. Treatment with either vitamin E or LD/CD significantly ameliorated behavioral, histopathological, and molecular abnormalities. Notably, the combination therapy elicited the most robust neuroprotective effects, exceeding the efficacy of monotherapies. Our data affords the molecular basis for managing PD by vitamin E add-on therapy with LD/CD, a strategy that could potentially reduce the need for higher LD/CD doses to overcome wearing-off and may even imply a dose reduction, thereby minimizing the risks of high-dose LD/CD monotherapy.