Irisin is a hormone-like peptide secreted by muscle tissues and generated by hydrolysis of type III fibronectin domain-containing protein 5 by proteolytic hydrolases. Whether Irisin has a potential protective role in traumatic brain injury (TBI). In this study, we will investigate the relevant research progress of Irisin's protective role in traumatic brain injury (TBI) in recent years in terms of attenuating oxidative stress, inhibiting pyroptosis, suppressing inflammatory response, and improving autophagy, with the aim of providing valuable references for the diagnosis and treatment of traumatic brain injury (TBI). Utilize bioinformatics analysis to study the interactions between genes in TBI (Traumatic Brain Injury). Construct a TBI mouse model to observe the effects of Irisin on TBI. The Morris water maze test is used to assess the learning and spatial memory abilities of mice, TUNEL fluorescence is used to detect cell apoptosis, Nissl staining is employed to observe the survival of hippocampal neurons in mice, and HE staining is used to observe the extent of brain injury in mice. Western blot is used to detect protein expression in both in vivo and in vitro experiments. Q-PCR is employed to detect the levels of proteins related to autophagy/pyroptosis/inflammation. Irisin promotes MerTK overexpression by enhancing AMPK activation. Irisin can increase the expression of LC3I and Beclin-1 proteins, indicating the promotion of autophagic response. Additionally, Irisin reduces ROS levels and decreases SYK expression, thereby inhibiting the inflammatory response. Irisin improves the learning and spatial memory abilities of TBI mice and reduces cell apoptosis, as well as decreases hippocampal neuron death. HE staining shows that the brain injury in mice treated with Irisin is significantly alleviated. Irisin can enhance the expression of phosphorylated AMPK and phosphorylated MerTK proteins, promote autophagic response, and inhibit pyroptosis/inflammatory response. Correction experiments confirmed that after stimulation with an AMPK agonist, the expression of phosphorylated MerTK protein is significantly increased, autophagic response is enhanced, and pyroptosis/inflammatory response is weakened. When treated with a MerTK inhibitor during AMPK agonist stimulation, the autophagic response is weakened while pyroptosis/inflammatory response is enhanced. Irisin can inhibit the progression of traumatic brain injury by regulating AMPK/MerTK/autophagy and SYK/ROS/inflammatory signaling.