Progesterone (P4) has shown promising results in diminishing the effects of cerebral hypoperfusion (CH) in prefrontal cortex. Therefore, our goal was to further analyze the neuroprotective mechanism of P4 in adult Wistar rats following bilateral occlusion of common carotid arteries (2VO). We investigated its impact on neurological function and activity of striatal extracellular purine metabolizing enzymes, CD39 and CD73. Following either sham or 2VO operation, for 7 consecutive days, animals (n=12) received s.c. treatments of commercial flax oil (V, 1 mg/kg) (Sham+V and 2VO+V groups) or 1.7 mg/kg P4 dissolved in V (2VO+P4 group). In 2VO+V animals, neurological deficits on 7th day were evident compared to the Sham+V group (p < 0.01); however, P4 treatment ameliorated deficits compared to 2VO+V (p < 0.05) and showed no difference compared to Sham+V. As indicators of CD39 activity, the hydrolysis rates of ATP and ADP were elevated in 2VO+V group compared to Sham+V (p < 0.01 for ATP; p < 0.05 for ADP) and 2VO+P4 (p < 0.05 for ATP) groups. Moreover, CD73, which hydrolyzes AMP to adenosine, showed increased activity in 2VO+P4 group compared to Sham+V (p < 0.001) and 2VO+V (p < 0.01) groups. Our data showed that P4 might moderate 2VO-initiated neuroinflammation by stimulating the production of adenosine, a potent anti-inflammatory and immunosuppressive compound that inhibits T cells proliferation, cytokine release, and leukocyte movement through endothelial barriers. Overall, our findings indicate that P4 could be a fundamental component of innovative therapeutic strategies for this type of brain injury.