A non-thermal high hydrostatic pressure (HHP) technology in combination with polysaccharidases is proposed as a novel approach to improve the phytochemical extraction from red macroalgae. Two macroalgae species, palmata palmata and Solieria chordalis, were hydrolyzed with cellulase and hemicellulase (separately or in combination) under HHP (400 MPa, 20 min). The HHP-assisted enzymatic treatment improved the extraction of specific molecules such as proteins, polyphenols and polysaccharides, but their effects are highly dependent on the macroalgae species. Consequently, the antioxidant activity of extracted fractions was improved by over 2.8 times for the treatment with HHP with hemicellulase. Antioxidant activity was highly correlated with polysaccharide (89%) and protein (83%) contents for S. chordalis, and with polyphenol (65%) for P. palmata. Our experiments demonstrated, for the first time, the potential of HHP-assisted enzymatic extraction of various phytochemicals from red macroalgae and the fact that their effects are highly dependent on the macroalgae species used.