This study is to investigate the protective effects of the SB203580 against radiation induced mortality and intestinal injury of mice.  A total of 67 male C57BL/6 mice (20.0−22.0 g) were matched according to body weight and randomly assigned to one of three groups: control, total body irradiation exposure (IR, 7.2Gy) only, and IR (7.2Gy) + SB203580 (15 mg?kg⁻¹).  30 days survival rate was observed in the experiment.  In intestinal injury experiment, the expression levels of caspase-3, Ki67, p53 and p-p38 were assayed in the mice intestine crypts.  The results showed that the 30 days survival rate was 100% (control), 0 (IR) and 40% (IR + SB203580), separately.  Compared to the IR groups, the positive cells of caspase-3, p53 and p-p38 in crypt cells decreased 33.00%, 21.78% and 34.63%, respectively.  The rate of positive cells of Ki67 increased 37.96%.  Significant difference was found between all of them (P < 0.01).  SB203580 potently protected against radiation- induced lethal and intestinal injury in mice, and it may be a potential radio protector.