Neuroprotection is a key goal in the study of neurodegenerative diseases such as Parkinson’s disease (PD), where progressive dopaminergic neuron loss causes severe motor and cognitive deficits. Epidemiological studies suggest that consumption of Yerba Mate (Ilex paraguariensis, YM), as well as coffee and green tea, is associated with reduced PD risk. These beverages contain polyphenols, particularly chlorogenic acid (CGA), proposed to mediate neuroprotective effects. We previously showed that YM protects dopaminergic neurons in primary cultures, but the underlying mechanisms remain unclear, especially those involving neuronal survival and protein homeostasis. Here, we investigated whether YM and CGA modulate pathways relevant to neuroprotection, focusing on AMPK activation, autophagy, and α-synuclein (α-Syn) aggregation. SH-SY5Y cells were used to evaluate AMPK phosphorylation after treatment with YM or CGA, while autophagy was assessed by LC3 ICC. In parallel, α-Syn aggregation was analyzed in H4 cells co-transfected with SynT and Synphilin-1. YM and CGA increased AMPK phosphorylation, suggesting activation of survival pathways. ICC revealed more LC3-positive puncta, indicating autophagy induction. In H4 cells, YM and CGA reduced the number and size of α-Syn aggregates. Altogether, these findings support that YM and CGA stimulate AMPK signaling, promote autophagy, and attenuate protein aggregation, highlighting YM as a promising dietary candidate for further studies in PD.