Creatine supplementation combined with exercise significantly improved motor function (p < 0.01) and increased tyrosine hydroxylase levels in Parkinson’s disease mice. It reduced necroptosis markers (MLKL, RIPK1/RIPK3) and α-synuclein aggregation (p < 0.01), suppressed inflammation (p < 0.01), and enhanced antioxidant enzyme levels via AMPK/Nrf2 and SIRT3/FoxO3a pathways (p < 0.01), showing additive neuroprotective effects. Here, FOXO3 is linked to Parkinson disease.