Background The interaction between urinary microcrystals and renal epithelial cells is closely related to kidney stone formation. However, the mechanism of cell state changes that affect crystal–cell interaction remains unclear. Methods This study investigated the relationship between the sulfate group (–OSO 3 − ) content in Porphyra yezoensis polysaccharide (PYP) and the ability to repair damaged cells, as well as the changes in cell adhesion and endocytosis of nano-calcium oxalate monohydrate (COM) crystals before and after PYP repair of damaged renal tubular epithelial cells. The sulfur trioxide–pyridine method was used to sulfate PYP (–OSO 3 − content of 14.14%), and two kinds of sulfated PYPs with –OSO 3 − content of 20.28% (SPYP1) and 27.14% (SPYP2) were obtained. The above three PYPs were used to repair oxalate-damaged human proximal tubular epithelial cells (HK-2), and the changes in the biochemical indicators of the cells before and after the repair and the changes in cell adhesion and endocytosis of nano-COM crystals were detected. Results After repair by PYPs, the cell viability increased, the number of reactive oxygen species decreased, and the reduction of mitochondrial membrane potential and the release of intracellular Ca 2+ were suppressed. The cells repaired by PYPs inhibited the adhesion of nano-COM crystals while promoting the endocytosis of the adhered crystals. The endocytosed crystals mainly accumulated in the lysosome. The ability of PYPs to repair cell damage, inhibit crystal adhesion, and promote crystal endocytosis was enhanced when the –OSO 3 − content increased. Among them, SPYP2 with the highest –OSO 3 − content showed the best biological activity. Conclusion SPYP2 showed the best ability to repair damaged cells, followed by SPYP1 and PYP. SPYP2 may become a potential green drug that inhibits the formation and recurrence of calcium oxalate stones.