Parkinson's disease (PD) is a motor system disorder caused by factors that lead to depletion of dopamine from the dopaminergic neurons in the substantia nigra. Mechanisms of PD include mitochondrial dysfunction, oxidative stress and neuroinflammation. Metformin is an old antidiabetic drug that has recently been shown to offer protective effects against many types of cancer, cardiovascular and neurodegenerative diseases. Indole-3-carbinol (I3C) is a phytochemical derived from the cruciform vegetables. Recently, I3C was proven to have antioxidant, anti-inflammatory and neuroprotective properties. The aim of this work was to study the effect of metformin and/or I3C on 6-hydroxydopamine (6-OHDA)-induced PD in rats. Sixty male Wistar rats were divided into 6 equal groups: Control; 6-OHDA, metformin + 6-OHDA; I3C + 6-OHDA; carboxymethyl cellulose + 6-OHDA and metformin + I3C + 6-OHDA group. Striatal dopamine, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), transforming growth factor beta1 (TGF-β1), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione reductase (GR), mitochondrial complex 1 activity, total swim score and catalepsy score were measured. The striatum was subjected to immunohistochemical examination. The combination between metformin and I3C induced significant increase in striatal SOD, GR, mitochondrial complex 1 activity and dopamine with significant decrease in striatal TNF-α, IL-6, TGF-β1, MDA and nuclear factor kappa-B expression with significant improvement in catalepsy and total swim scores better than the groups that received either I3C or metformin alone. So, metformin/I3C combination may represent a beneficial therapeutic modality for amelioration of 6-OHDA-induced PD in rats.