AbstractParkinson's disease (PD) is a common neurodegenerative disease with limited treatment and no cure, hence, broadening PD drug spectrum is of great significance. At present, engineered microorganisms are attracting increasing attention. In this study, we constructed an engineered strain ofClostridium butyricum‐GLP‐1, aC. butyricum(a probiotic) that consistently expresses glucagon‐like peptide‐1 (GLP‐1, a peptide‐based hormone with neurological advantage) in anticipation of its use in PD treatment. We further investigated the neuroprotective mechanism ofC. butyricum‐GLP‐1 on PD mice models induced by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine. The results indicated thatC. butyricum‐GLP‐1 could improve motor dysfunction and ameliorate neuropathological changes by increasing TH expression and reducing the expression of α‐syn. Moreover, we confirmed thatC. butyricum‐GLP‐1 improved microbiome imbalance of PD mice by decreasing the relative abundance ofBifidobacteriumat the genus level, improved gut integrity, and upregulated the levels of GPR41/43. Surprisingly, we found it could exert its neuroprotective effects via promoting PINK1/Parkin mediated mitophagy and attenuating oxidative stress. Together, our work showed thatC. butyricum‐GLP‐1 improves PD by promoting mitophagy, which provides an alternative therapeutic modality for PD.