The ability of cannabinoid CB1 receptors to influence glutamatergic excitatory neurotransmission has fueled interest in how these receptors and their endogenous ligands may interact in conditions of excitotoxic insults. The present study characterized the impact of stimulated and inhibited CB1 receptor function on NMDA-induced excitotoxicity. Neonatal (6-day-old) rat pups received a systemic injection of a mixed CB1/CB2 receptor agonist (WIN55,212–2) or their respective antagonists (SR141716A for CB1 and SR144528 for CB2) prior to an unilateral intrastriatal microinjection of NMDA. The NMDA-induced excitotoxic damage in the ipsilateral forebrain was not influenced by agonist-stimulated CB1 receptor function. In contrast, blockade of CB1, but not CB2, receptor activity evoked a robust neuroprotective response by reducing the infarct area and the number of cortical degenerating neurons. These results suggest a critical involvement of CB1 receptor tonus on neuronal survival following NMDA receptor-induced excitotoxicity in vivo.