We observed that on long-term breeding, gp91phox-knockout (gp91phox−/−) mice developed white hair. Here, we investigate the origin of this hitherto unexplained phenomenon. Moreover, we investigated the effect of tranexamic acid administration on the hair color in gp91phox−/− mice. We administered tranexamic acid (about 12 mg/kg/day) orally to 9-week-old C57BL/6j (control) and gp91phox−/− mice, thrice a week for 12 months. Compared to control mice, gp91phox−/− mice showed more white hair. However, the concentrations of reactive oxygen species and the levels of interleukin (IL)-1β and transforming growth factor (TGF)-β in the skin were lower than those in the control group. Furthermore, increase in white hair was observed in the control mice upon administration of the IL-1β antagonist. On the other hand, administration of tranexamic acid led to brown colored hair on gp91phox−/− mice. Although tranexamic acid treatment did not alter the expression levels of melanocortin receptor 1 and agouti signaling protein on hair follicles, it increased the expression of mahogunin ring finger protein 1 (MGRN1) and collagen XVII. These results suggested that retention of black hair requires the gp91phox/ROS/IL-1β/TGF-β pathway and that elevated levels of MGRN1 and collagen XVII lead to brown hair in gp91phox−/− mice.