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A majority of blast-induced mild traumatic brain injury (mTBI) patients experience persistent neurological dysfunction with no findings on conventional structural MR imaging. It is urgent to develop advanced imaging modalities to detect and understand the pathophysiology of blast-induced mTBI. Fluorine-18 fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) could detect neuronal function and activity of the injured brain, while MR spectroscopy provides complementary information and assesses metabolic irregularities following injury. This study aims to investigate the effectiveness of combining 18 F-FDG PET with MR spectroscopy to evaluate acute and subacute metabolic cerebral alterations caused by blast-induced mTBI. Thirty-two adult male Sprague-Dawley rats were exposed to a single blast (mTBI group) and 32 rats were not exposed to the blast (sham group), followed by 18 F-FDG PET, MRI, and histological evaluation at baseline, 1-3 h, 1 day, and 7 days post-injury in three separate cohorts. 18 F-FDG uptake showed a transient increase in the amygdala and somatosensory cortex, followed by a gradual return to baseline from day 1 to 7 days post-injury and a continuous rise in the motor cortex. In contrast, decreased 18 F-FDG uptake was seen in the midbrain structures (inferior and superior colliculus). Analysis of MR spectroscopy showed that inflammation marker myo-inositol (Ins), oxidative stress marker glutamine + glutamate (Glx), and hypoxia marker lactate (Lac) levels markedly elevated over time in the somatosensory cortex, while the major osmolyte taurine (Tau) level immediately increased at 1-3 h and 1 day, and then returned to sham level on 7 days post-injury, which could be due to the disruption of the blood-brain barrier. Increased 18 F-FDG uptake and elevated Ins and Glx levels over time were confirmed by histology analysis which showed increased microglial activation and gliosis in the frontal cortex. These results suggest that 18 F-FDG PET and MR spectroscopy can be used together to reflect more comprehensive neuropathological alterations in vivo , which could improve our understanding of the complex alterations in the brain after blast-induced mTBI., Competing Interests: The reviewer CZ declared a past co-authorship with one of the author FJ to the handling editor. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Liu, Li, Guo, Fang, Tong, Tang, Zhang, Sun, Jiao, Zhang, Jin, Xiong and Chen.)