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S. cerevisiae -derived-beta- d -glucan (S. cerevisiae -BG) is a natural polysaccharide with various biological effects. The present study was to investigate the protective effect of S. cerevisiae -BG on the injury induced by high linear-energy-transfer (LET) carbon ion irradiation and to reveal the protective mechanisms. Female mice were orally administrated with S. cerevisiae -BG before irradiation. 30-day survival of 6 Gy irradiated-mice was monitored. The damage and recovery of hematopoietic system were evaluated after 2 Gy irradiation, cytokines in plasma were detected, transcriptomics of bone marrow mononuclear cells (BMMNCs) were detected and analyzed. The mortality results showed that S. cerevisiae -BG could prolong the survival of mice exposed to 6 Gy. The results of BMMNCs injury analysis showed that S. cerevisiae -BG could reduce the ROS level, mitigate DNA damage and apoptosis. S. cerevisiae -BG increased the plasma radioprotective cytokines level in irradiated mice. Transcriptomics analysis revealed that S. cerevisiae -BG modulated the gene expression in BMMNCs of irradiated mice, 256 genes were significantly up-regulated and 97 genes were significantly down-regulated. Gene function and Gene Ontology analysis indicated the key genes related to hematopoiesis and immunity. Pathway analysis revealed that these up-regulated genes mainly focus on PI3K-Akt pathway and down-regulated genes mainly focus on MAPK pathway. These data contribute to understanding the molecular mechanisms of the radioprotective effect of S. cerevisiae -BG. • S. cerevisiae -BG prolonged the survival of carbon ion irradiated mice. • S. cerevisiae -BG ameliorates carbon ion irradiation-induced murine myelosuppression. • S. cerevisiae -BG affected transcriptomic response of radiotoxicity in bone marrow. • S. cerevisiae -BG mainly regulated PI3K-Akt and MAPK pathway for radioprotection. [ABSTRACT FROM AUTHOR]