Aim:Contusional expansion (CE) is a complex and preventable secondary injury. However, current treatments for CE focus on reducing intracranial hypertension and are not preventive, largely because the molecular mechanisms involved remain poorly understood. This study aimed to provide insight into the molecular mechanism of CE by creating experimentally induced contusion cerebri (CC) in rats and investigating whether melatonin administration prevents CE.Material and Methods:Rats were randomized into four groups: Group 1 (control, n=5), group 2 (trauma, n=25), group 3 (trauma plus placebo, n=25), and, group 4 (trauma plus melatonin, n=25). Rats in the control group were sacrificed without undergoing any invasive procedure. Groups 2, 3, and 4 were further divided into 5 subgroups (A–E), with animals in each sacrificed at 12, 24, 72, 120, and 168 h after CC induction. Samples from these subgroups were analyzed for levels of caspase 3, caspase 8, and matrix metalloproteinase-9, as well as for evidence of ischemia, blood-brain barrier (BBB) breakdown, vasogenic edema (VE), and hemorrhage. Temporal progression of CE and correlations between these variables were also investigated.Results:Our results indicated that the ischemia, BBB breakdown, and VE are early events that initiate CE, with VE and hemorrhagic transformation due to BBB breakdown identified as key factors. Melatonin treatment prevented CE injury.Conclusion:Melatonin, a safe and well-tolerated substance with minimal toxicity, may serve as a potential therapeutic agent for preventing CE injury.