Objective We investigated the effects of recombinant human erythropoietin (rhEPO) on inflammatory factors and mitochondrial damage in the brain tissue of rats with traumatic brain injury. Methods Sprague-Dawley rats were randomly divided into three groups, 15 in each group: a sham operation group (sham group), a model group, and a rhEPO intervention group ( treatment group). The rats in the model group and the treatment group were subjected to a modified Feeney weight-drop model, in which the head strike establishes the traumatic rat model; the sham group was not subjected to this head strike. At the end of modeling, the treatment group was intraperitoneally injected with rhEPO at a dose of 5 000 IU/ kg daily. The sham group and the model group were intraperitoneally injected with an equal amount of normal saline. The rats were sacrificed seven days after continuous administration. rhodamine 123(Rh123) staining was used to detect changes in mitochondrial membrane potential. Immunohistochemistry was used to detect the expression of interleukin-1β(IL-1β), interleukin-6( IL-6), and tumor necrosis factor-α( TNF-α) in the brain tissue of each group. Western blot analysis was used to detect the protein expression levels of dynamin-related protein 1 (Drp1), mitochondrial fission 1 protein ( Fis1), mitochondrial fusion protein 2 ( Mfn2), and optic atrophic protein 1 ( Opa1). Results Compared with the sham group, the Rh123 fluorescence intensity of brain tissue cells in the model group was significantly weakened, the expressions of IL-1β, IL-6, TNF-α, Drp1, and Fis1 proteins were significantly increased, and the expressions of MFN2 and OPA1 proteins were significantly decreased (all P< 0. 05). Compared with the model group, the Rh123 fluorescence intensity of brain tissue cells in the treatment group was significantly increased, the expressions of IL- 1β, IL-6, TNF-α, Drp1, Fis1 proteins were significantly decreased, and the expressions of Mfn2 and OPA1 proteins were significantly increased (all P< 0. 05). Conclusions Recombinant human erythropoietin can reduce inflammatory response and mitochondrial damage after traumatic brain injury, thereby playing a protective role in brain tissue after traumatic brain injury.