Argentina’s extensive coastline harbors diverse macroalgae, with the red seaweed (Rhodophyceae) Pyropia columbina being particularly prominent in Patagonia. Seaweed composition varies with environmental and processing conditions. It is known to contain proteins, fiber, vitamins, minerals, and relatively low lipid content. In recent years, seaweed has also been studied due to its content of phenolic compounds, which can be harnessed as antioxidants for potential nutraceutical applications and the prevention of chronic diseases. Different extraction methods can be used for this purpose, among which pressurized liquid extraction (PLE) stands out as a greener option. The aim of this study was to determine the optimal extraction conditions through PLE using ethanol–water mixtures for seaweed Pyropia columbina, with a focus on its antioxidant activity. Extraction was performed at varying ethanol concentrations (50–100%) and temperatures (100–140°C). Extraction yield (%/g), total phenolic content (TPC) using the Folin–Ciocalteu method (mg GAE/g), and radical scavenging activity via the ABTS assay (mg TEAC/g) were determined. Optimal conditions were assessed through the application of Expert Design (ED) methodology. Extraction yield varied across conditions, ranging from 4.3% (100% EtOH, 100°C) to 70.9% (50% EtOH, 140°C). Regarding TPC and ABTS, 100% Ethanol at 140°C was the sample with the highest values (20.25±1.33 mg GAE/g and 151.55±5.24 mg TEAC/g) (∝<0.05). Using ED, optimal conditions were 94% Ethanol at 140°C for TPC (0.98 desirability) and 73% at 140°C for TEAC (0.94 desirability). To optimize both parameters, final conditions were set at 83.5% EtOH and 140°C. A new extract with 41.8% yield, 18.24±1.79 mg GAE/g, and 141.21 ± 6.97 mg TEAC/g was obtained. Model validation confirmed the predicted values, supporting optimal conditions for antioxidant extraction from Pyropia columbina via PLE with satisfactory yield.