Introduction:  Traumatic brain injury (TBI) is defined as a change in brain function, or the presence of another brain pathology as a result of an external force (Menon et al., 2010). Oxidative stress, inflammation, and apoptosis following TBI lead to further deterioration of brain damage. Antiinflammatory and neuroprotective activity of the plasminogen activator inhibitor-1 (PAI-1) antagonist in neuroinflammatory animal models has been reported (Chan et al., 2018; Pelish et al., 2015). Aims/Objectives: In this study, it was aimed to investigate possible protective effects of PAI-1 antagonist in a rat TBI model. Method: Sprague Dawley male rats were grouped as sham (n=7), TBI (n=9), TBI + PAI-1 antagonist (5 or 10 mg/kg TM5441 or TM5484; n=6-7). Under anesthesia, TBI was induced by weight-drop model and the rats were decapitated after 24-hour. Before and 24-hour after trauma neurological examination, tail suspension, Y-maze, novel object recognition tests were performed. Activities of myeloperoxidase, nitric oxide levels, 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 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. Results: Higher levels myeloperoxidase activity in the trauma group (p<0.05) were found to be suppressed in 5 and 10 mg/kg TM5441 treatment groups (p<0.05-p<0.01). The tail suspension test score was increased in trauma 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 trauma 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, are effective for some biological markers and behavioral tests after TBI. Examining the effects of PAI-1 inhibition on both pathophysiological and functional outcomes in TBI and obtaining promising results shed light on future clinical studies.