Utilizing the energy released from the nuclear fusion of deuterium with tritium (D-T) may be an important method of supplying energy in the future. The ionizing radiation emitted from nuclear fusion is a potential health risk to humans, including scientists who are currently performing nuclear fusion experiments and the employees of fusion nuclear plants, in the future. However, there have been few reports on the biological effects of fusion radiation. In the present study, using the High Intensity D-T Fusion Neutron Generator, the DNA damage and its regulation in normal human fibroblasts exposed to fusion radiation were investigated. Heme oxygenase 1 (HO-1), which is reported to induce anti-inflammatory activity, was upregulated in the irradiated cells. Pretreatment with the HO-1 inhibitor, protoporphyrin IX zinc (II), exacerbated double strand break formation following exposure to fusion radiation. The expression of cyclooxygenase-2 (COX-2) contributed to the upregulation of HO-1, as demonstrated by the result that its inhibitor, NS-398, inhibited the induction of HO-1 in irradiated cells. It was further clarified that the ataxia telangiectasia mutated DNA damage response was activated and it stimulated the phosphorylation of p38 mitogen-activated protein kinase, which was responsible for the upregulation of COX-2 and HO-1. These results provide novel information on fusion radiation-induced biological effects and potential targets for decreasing the associated health risks.