There are multiple associations between the different blood groups (ABO and RhD) and the incidence of oxidative stress-related diseases, such as certain carcinomas and COVID-19. Bioactive compounds represent an alternative to its prevention and treatment. Phycobiliproteins (PBP) are bioactive compounds present in the microalga Porphyridium cruentum and, despite its antioxidant activity, their inhibitory effect on hemolysis has not been reported. The aim of this work was to evaluate the erythroprotective potential of phycobiliproteins from P. cruentum in different blood groups. The microalga was cultured in F/2 medium under controlled laboratory conditions. Day 10 of culture was determined as the harvest point. The microalgal biomass was lyophilized and a methanolic (MetOH), Tris HCl (T-HCl), and a physiological solution (PS) ultrasound-assisted extraction were performed. Extract pigments were quantified by spectrophotometry. The antioxidant activity of the extracts was evaluated with the ABTS+•, DPPH•, and FRAP methods, finding that the main antioxidant mechanism on the aqueous extracts was HAT (hydrogen atom transfer), while for MetOH it was SET (single electron transfer). The results of the AAPH, hypotonicity, and heat-induced hemolysis revealed a probable relationship between the different antigens (ABO and RhD) with the antihemolytic effect, highlighting the importance of bio-directed drugs.