SummaryNon‐motor symptoms including those involving the splanchnic district are present in Parkinson's disease (PD). The authors previously reported that PD‐like rats, bearing a lesion of the nigrostriatal pathway induced by the injection of 6‐hydroxydopamine (6‐OHDA), have impaired hepatic mitochondrial function. Glutamate intervenes at multiple levels in PD and liver pathophysiologies. The metabotropic glutamate receptor 5 (mGluR5) is abundantly expressed in brain and liver and may represent a pharmacological target for PD therapy. This study investigated whether and how chronic treatment with 2‐methyl‐6‐(phenylethynyl)‐pyridine (MPEP), a well‐characterized mGluR5 antagonist, may influence hepatic function with regard to neuronal cell loss in PD‐like rats. Chronic treatment with MPEP was started immediately (Early) or 4 weeks after (Delayed) intrastriatal injection of 6‐OHDA and lasted 4 weeks. Early MPEP treatment significantly prevented the decrease in adenosine triphosphate (ATP) production/content and counteracted increased reactive oxygen species (ROS) formation in isolated hepatic mitochondria of PD‐like animals. Early MPEP administration also reduced the toxin‐induced neurodegenerative process; improved survival of nigral dopaminergic neurons correlated with enhanced mitochondrial ATP content and production. ATP content/production, in turn, negatively correlated with ROS formation suggesting that the MPEP‐dependent improvement in hepatic function positively influenced neuronal cell survival. Delayed MPEP treatment had no effect on hepatic mitochondrial function and neuronal cell loss. Antagonizing mGluR5 may synergistically act against neuronal cell loss and PD‐related hepatic mitochondrial alterations and may represent an interesting alternative to non‐dopaminergic therapeutic strategies for the treatment of PD.