Exposure to ionizing radiation is a major threat to human health and public security. Since the inherent limitations of current methods for indicating radiation exposure, new minimally invasive biomarkers that can be easily and quickly detected at an early stage are needed for optimal medical treatment. Serum proteins are attractive biomarkers and some radiosensitive proteins have been found, but the proteins in response to low-dose and high-linear energy transfer (LET) radiation have not been reported. In this study, mice were whole body exposed to a variety doses of carbon ions and X-rays. We performed Mouse Antibody Array to detect serum proteins expression profiles at 24 hours postirradiation. After conditional screening, insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-1 (IGFBP-1), and IGFBP-3 were further validated using enzyme-linked immunosorbent assay. After exposure to 0.05 to 1 Gy of carbon ions and 0.5 to 4 Gy of X-rays, only IGFBP-3 showed obvious increase with increased doses, both carbon ions and X-rays. Further, IGFBP-3 was detected for observation of its time-dependent changes. The results showed the expression difference of IGFBP-3 presented from 6 to 24 hours post-irradiation by carbon ions and X-rays. Moreover, the receiver-operating characteristic analysis showed that serum IGFBP-3 is efficient to triage exposed individuals with high sensitivity and specificity. These results suggest that serum IGFBP-3 is extremely sensitive to high- and low-LET ionizing radiation and is able to respond at an early stage, which could serve as a novel minimally invasive indicator for radiation exposure.