Endocannabinoids are involved in synaptic signaling and neuronal protection, however, our understanding of the mechanisms by which endocannabinoids protect neurons from harmful insults remains elusive. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid and a full agonist for cannabinoid receptors (CB1 and CB2), is a substrate for cyclooxygenase-2 (COX-2), and can be metabolized by COX-2. Here we show, however, that 2-AG is also capable of suppressing elevation of hippocampal COX-2 expression in response to proinflammatory and excitotoxic stimuli. 2-AG prevents neurodegeneration from toxic assaults that elevate COX-2 expression, and inhibits the COX-2 elevation-enhanced excitatory glutamatergic synaptic transmission. The action of 2-AG on suppression of COX-2 appears to be mediated via the pertussis toxin (PTX)-sensitive G protein-coupled CB1 receptor and Mitogen-activated protein kinases (MAPK)/nuclear factor-B (NF-B) signaling pathways. Our results reveal that 2-AG functions as an endogenous COX-2 inhibitor protecting neurons from harmful insults by preventing excessive expression of COX-2, which provides a mechanistic basis for opening up new therapeutic approaches of protecting neurons from inflammation- and excitotoxicity-induced neurodegeneration.