Parkinson's disease (PD), the most prevalent neurodegenerative disorder, affects over 7.5 million individuals worldwide and imposes a substantial financial burden. Exercise (EXE) has demonstrated efficacy in improving motor symptoms of PD; however, its application is limited by motor symptoms such as bradykinesia, rigidity, gait instability, and fatigue, which reduce patient tolerance and adherence. This highlights the need for accessible, non-invasive alternatives with similar efficacy. Remote ischemic conditioning (RIC), a low-cost, non-invasive intervention, has shown neuroprotective effects in stroke and cognitive impairment and may offer comparable benefits without these limitations. This study evaluates the therapeutic efficacy of RIC versus EXE in a PD mouse model.PD was induced in mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injections (30 mg/kg) for 5 days. Mice were assigned to four groups: Control, PD, EXE, and RIC. EXE involved treadmill training (30 mins, twice a day for 14 days), while RIC consisted of repeated limb ischemia-reperfusion cycles (3 occlusion-reperfusion cycles, for 14 days). Motor performance was assessed using rota-rod and open field tests. Neuroinflammatory markers, microglial activation, and oxidative stress were analyzed via immunofluorescence, ELISA, and Western blot.Both RIC and EXE significantly improved motor function and attenuated dopaminergic neurodegeneration. These interventions reduced α-synuclein accumulation and restored tyrosine hydroxylase (TH) expression. Additionally, both interventions suppressed microglial activation, decreased iNOS/Iba-1 and IL-1β/Iba-1 expression, and downregulated the TLR4/NF-κB pathway and associated proinflammatory cytokines (IL-1β, IL-6, TNF-α). RIC and EXE also alleviated NOX-driven oxidative stress.RIC and EXE provide comparable neuroprotective effects in PD by suppressing TLR4-mediated neuroinflammation and oxidative damage. Given its non-invasive, low-cost nature and ease of administration, RIC may represent a promising rehabilitation strategy for patients with limited access to or tolerance for exercise-based therapies.Copyright © 2025. Published by Elsevier B.V.