Background/Objectives: Oxidative stress is a key pathogenic factor in gastric diseases (GDs). Nutraceuticals with antioxidant activity derived from macroalgae represent promising preventive strategies. However, Chilean macroalgae remains poorly explored in the context of GDs, particularly associated with oxidative stress. This study evaluated the antioxidant and cytoprotective properties of crude aqueous and ethanolic extracts from green, brown, and red macroalgae collected along the north-central coast of Chile. Methods: Crude extracts were prepared from green, brown, and red macroalgae and evaluated for antioxidant activity via ABTS, DPPH, and FRAP assays. Using hydrogen peroxide-induced oxidative stress in GES-1 gastric epithelial cells, we assessed cell viability (MTS assay), intracellular reactive oxygen species (ROS) levels (time-lapse confocal microscopy), and apoptosis (active caspase-3 detection). Results: All extracts exhibited antioxidant activity; the red macroalgae Gracilaria chilensis displayed the highest flavonoid content (up to 2.24 mg QE/g dw). Notably, extracts from G. chilensis, S. gaudichaudii, and M. canaliculata preserved GES-1 cell viability under hydrogen peroxide-induced stress, outperforming green and brown species, demonstrating the superior cytoprotective capacity of red macroalgae compared to other groups. Furthermore, G. chilensis extracts significantly reduced intracellular ROS levels and attenuated ROS-induced apoptosis. Conclusions: Red macroalgae extracts, particularly G. chilensis, exhibit strong antioxidant and cytoprotective effects. Our findings demonstrate that these species outperform green and brown macroalgae, addressing a gap in knowledge regarding Chilean marine resources. These results support their potential development as nutraceuticals for the prevention of oxidative stress-related gastric diseases and highlight red macroalgae as a valuable source of bioactive compounds for diet-based preventive strategies.
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