ETHNOPHARMACOLOGICAL RELEVANCE: Empirically, Ilex paraguariensis A. St. Hil, or yerba-mate, has been used by natives of South America as a stimulant. Nowadays, this plant has gained popularity due to its neuroprotective effects. However, there are few studies on the biochemical-molecular mechanisms of action involved in its effect. AIM OF THE STUDY: Chemically characterize an aqueous extract of yerba mate (YME) and evaluate if it could suppress the aberrant inflammatory response related to neurodegeneration. MATERIALS AND METHODS: Macrophages and microglia cells were exposed to lipopolysaccharide (LPS
100 ng/mL) plus nigericin (100 μM) or quinolinic acid (QA
5 mM). Cellular viability, oxidative, and inflammatory markers were evaluated. Chemical matrix (HPLC - DAD), antioxidant activity, safety profile in vitro and in vivo, and an in silico docking of main targets were also assessed. RESULTS: Pre-treatment with YME (15 μg/mL) prevented impairments in redox metabolism and inflammatory markers in BV-2 cells. In macrophages, YME showed similar results to MCC950, an inflammasome inhibitor. YME presented 282.88 mg EAG/g total phenolic content and a redox capacity of 32.94 ± 1.30 μg/mL (IC CONCLUSION: YME has significantly affected macrophages and microglia by regulating the NLRP3 inflammatory pathway.