This study isolates, purifies, and fractionates Polygonatum polysaccharides (PSPs) from Polygonatum sibiricum, and evaluates their hepatoprotective activity against CCL4-induced liver damage in HepG2 cells. Three homogeneous fractions, PSP-N-b-1, PSP-N-b-2, and PSP-N-c-1, were obtained through DEAE-cellulose, Sepharose CL-6B, and Sephadex G100 chromatography. These fractions were analyzed for monosaccharide composition and molecular weight, revealing they are primarily composed of Man, GlcA, Rha, GalA, Glc, and Ara, with molecular weights of 6.3 KDa, 5.78 KDa, and 3.45 KDa, respectively. The study demonstrates that Polygonatum polysaccharides exhibit protective effects against CCL4-induced liver damage in HepG2 cells through antioxidant and anti-inflammatory mechanisms. The results show that these polysaccharides can reduce the levels of liver enzymes (ALT and AST) and oxidative stress markers (MDA), while increasing antioxidant enzymes (SOD and CAT). Additionally, they significantly reduce the levels of inflammatory factors (TNF-α, IL-1β, and IL-6), indicating their potential as hepatoprotective agents. The study highlights the importance of further research to explore the mechanisms and applications of Polygonatum polysaccharides in liver protection and drug development. The findings suggest that these polysaccharides may serve as promising candidates for the development of hepatoprotective drugs or functional foods with anti-inflammatory and antioxidant properties.This study isolates, purifies, and fractionates Polygonatum polysaccharides (PSPs) from Polygonatum sibiricum, and evaluates their hepatoprotective activity against CCL4-induced liver damage in HepG2 cells. Three homogeneous fractions, PSP-N-b-1, PSP-N-b-2, and PSP-N-c-1, were obtained through DEAE-cellulose, Sepharose CL-6B, and Sephadex G100 chromatography. These fractions were analyzed for monosaccharide composition and molecular weight, revealing they are primarily composed of Man, GlcA, Rha, GalA, Glc, and Ara, with molecular weights of 6.3 KDa, 5.78 KDa, and 3.45 KDa, respectively. The study demonstrates that Polygonatum polysaccharides exhibit protective effects against CCL4-induced liver damage in HepG2 cells through antioxidant and anti-inflammatory mechanisms. The results show that these polysaccharides can reduce the levels of liver enzymes (ALT and AST) and oxidative stress markers (MDA), while increasing antioxidant enzymes (SOD and CAT). Additionally, they significantly reduce the levels of inflammatory factors (TNF-α, IL-1β, and IL-6), indicating their potential as hepatoprotective agents. The study highlights the importance of further research to explore the mechanisms and applications of Polygonatum polysaccharides in liver protection and drug development. The findings suggest that these polysaccharides may serve as promising candidates for the development of hepatoprotective drugs or functional foods with anti-inflammatory and antioxidant properties.