Ionizing radiation (IR) can produce superfluous reactive oxygen species (ROS) and induce oxidative damage to human health. In view of the shortcomings of chemosynthetic radioprotectors, natural radioprotectors have garnered attention due to their effectiveness, safety, and suitability for long-term use. Natural active substances, such as polysaccharides, polyphenols and alkaloids, have been proved exert good radioprotective effect. In the present study, the main components and monosaccharide compositions of the polysaccharides from Poria cocos peels (PCPP) and its radioprotective activities against 60Co-γ induced oxidative damage in vitro and in vivo were evaluated. The results showed that PCPP contained (63.13 ± 3.19)% of total sugar and was composed of mannose, arabinose, glucuronic acid, galacturonic acid, glucose, galactose and fucose in a molar radio of 104.84:1.34:2.83:1.00:290.48:243.30:79.63. Moreover, PCPP exhibited significant antioxidant activity and could significantly reduce the damage of AML-12 cells under IR. Animal experiment results showed that PCPP could effectively reduce IR-induced oxidative damage of spleens and livers in mice, and alleviate the damage to the hematopoietic system. Furthermore, PCPP could greatly increase the activity of superoxide dismutase (SOD) and the content of glutathione (GSH) in serum, livers and spleens of 60Co-γ induced mice, and correspondingly reduce the accumulation of malondialdehyde (MDA), along with the prominent reduction of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and livers in mice. Above results comprehensively indicated that PCPP exerted significant antioxidant activity and could effectively reduce the 60Co-γ induced damage in vitro and in vivo.