Introduction: Plasminogen activator inhibitor-1 (PAI-1) antagonists are known for their neuroprotective effects. Demonstration of a role for PAI-1 in the pathophysiology of inflammation as well as cerebrovascular injury drove considerable attention to the development of PAI-1 antagonists and no studies are testing the possible anti-inflammatory actions of PAI-1 antagonists during the secondary brain injury after TBI. Aims/objectives: In this study, it was aimed to investigate the possible protective effects of PAI-1 antagonists in a rat mild traumatic brain injury (TBI) model. Method: Sprague Dawley male rats were grouped as sham (n=7), TBI (n=9), TBI + PAI-1 antagonist (5 and 10 mg/kg TM5441 and TM5484; n=6-7). All experimental procedures used in this investigation were reviewed and approved by the Marmara University Animal Care and Use Committee (12.2019.mar). Animal care and all experiments were conducted in concordance with the principles of the World Medical Association’s Declaration of Helsinki. Under anesthesia, TBI was induced by dropping a metal 300-gram weight from a height of 1 meter on the skull. Before and 24-hour after trauma neurological examination, tail suspension, Y-maze, novel object recognition tests were performed. Twenty-four hours after TBI, the rats were decapitated and activities of myeloperoxidase, nitric oxide release, luminol- and lucigenin-enhanced chemiluminescence were measured. Also, interleukin-1b, interleukin-6, tumor necrosis factor, interleukin-10, tumor growth factor-b, caspase-3, cleaved caspase-3, and PAI levels were measured with the ELISA method in the brain tissue. Brain injury was graded histopathologically following hematoxylin-eosin staining. Western blot and immunohistochemical investigation for low-density lipoprotein receptor, matrix metalloproteinase-3 ve nuclear factor-kB were also performed. Data were analyzed using GraphPad Prism 8.0 (GraphPad Software, San Diego, CA, USA) and expressed as means ± SEM. Values of p < 0.05 were considered to be statistically significant. Results: Higher levels of myeloperoxidase activity in the TBI group (p<0.05) were found to be suppressed in 5 and 10 mg/kg TM5441treatment groups (p<0.05-p<0.01). The tail suspension test score was increased in the TBI group (p<0.001), and decreased in all treatment groups (p<0.05-0.001).  The histologic damage score was increased statistically significantly in the cortex, dentate gyrus, and CA3 regions in the TBI group (p<0.01-0.001), decreased in the treatment groups in the cortex and dentate gyrus (p<0.05-0.001).  Conclusion: PAI antagonists, especially TM5441, has antioxidant and anti-inflammatory properties against mild TBI in the acute period. Behavioral test results were also improved after PAI antagonist treatment after mild TBI.