This review summarizes recent developments that have contributed to our understanding of how adenosine 2A receptors (A2ARs) modulate brain damage in various animal models of acute neurological injuries, including brain ischemia, traumatic brain injury, spinal cord injury and hemorrhage stroke. The main conclusions are: (1) pharmacological, neurochemical and molecular/genetic approaches to the complex actions of A2AR in different cellular elements suggest that A2AR activation exerts bidirectional effect (detrimental or protective) after brain insults; (2) modulation of glutamate excitotoxicity and neuroinflammation are involved in the protection of A2AR agonists or antagonists, but the bidirectional effect of A2AR is largely due to the bidirectional regulation of neuroinflammation (anti-inflammation or proinflammation) by A2AR on immune cells such as microglia cells and peripheral bone marrow cells; and (3) the bidirectional effect of A2AR on neuroinflammation and brain injury depends on the distinct and sometimes opposite actions of A2AR in various cellular elements and on different injury models and associated pathological conditions. The local glutamate level in the brain injury is one of the crucial factors that contribute to the direction of A2AR effect on neuroinflammation and brain injury outcome. These developments presented here clearly highlight the complexity of using A2AR agents therapeutically in acute neuronal injuries and confirm that A2AR ligands have many promising characteristics that encourage the pursuit of their full therapeutic potential.