Oxidative stress and neuroinflammation have been proposed as key mechanisms underlying the dysfunction and death of dopaminergic neurons in the substantia nigra, leading to the development of Parkinson’s disease. Yerba mate (YM) consumption has been associated with multiple health benefits, largely attributed to its bioactive compounds with strong antioxidant activity. In a hemiparkinsonian mouse model, we previously observed that chronic treatment with YM exerts neuroprotective effects on dopaminergic neurons. The present study aimed to determine whether neuroprotection induced by YM extract is associated with a favorable modulation of oxidative stress, either through the enhancement of antioxidant enzyme activity and/or neutralizing free radicals. For this purpose, C57BL6J mice received an extract of YM or water for 4 months. Then, a moderate dopaminergic lesion was induced by intrastriatal 6-OHDA injection and treatments were continued until sacrifice at 2 or 30 days post-lesion. Antioxidant capacity (ABTS), oxidative damage (TBARS) and enzymatic antioxidant systems (GPx, GR, SOD) were measured in striatal tissue homogenates. Our findings indicate that animals treated with YM showed a positive modulation of enzymatic antioxidant systems, which may be associated with enhanced antioxidant capacity and reduced lipid oxidative damage. These findings support the role of YM as a potential neuroprotective agent against oxidative stress–related dopaminergic degeneration.