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Traumatic brain injury (TBI) can lead to disability or devastating consequences with few established treatments. Although ferroptosis has been shown to be involved in TBI, the underlying mechanism was rarely known. Melatonin has been indicated to exhibit neuroprotective activities. However, the anti-ferroptotic effects of melatonin on TBI have not yet to be elucidated. We aimed to investigate whether ferroptosis was induced in humans after TBI and whether ferroptosis inhibition by melatonin could protect against blood-brain barrier (BBB) damage after TBI in vivo and in vitro. Circular RNAs (circRNAs) are highly expressed in the brain. For the first time, differentially expressed circRNA after melatonin treatment for TBI were detected by RNA sequencing. We found that lipid peroxidation was induced in humans after TBI, while melatonin significantly improved brain function of mice after TBI and alleviated ferroptosis and endoplasmic reticulum (ER) stress in vivo and in vitro. A total of 1826 differentially expressed circRNAs were found (fold change2, Q 0.01), including 921 down-regulated and 905 up-regulated circRNAs in the injured brain tissues of TBI mice receiving melatonin treatment. Mechanistically, melatonin administration reduced the level of circPtpn14 (mmu_circ_0000130), which functioned by acting as a miR-351-5p sponge to positively regulate the expression of the ferroptosis-related 5-lipoxygenase (5-LOX). Moreover, circPtpn14 overexpression partly abolished the inhibitory effects of melatonin on ferroptosis. Collectively, our findings provide the first evidence that melatonin could exert anti-ferroptotic and anti-ER stress effects in brain injury by alleviating lipid peroxidation via the circPtpn14/miR-351-5p/5-LOX signaling.