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Maladaptive fear generalization is one of the hallmarks of trauma-related disorders. The endocannabinoid 2-arachidonoylglycerol (2-AG) is crucial for modulating anxiety, fear, and stress adaptation but its role in balancing fear discrimination versus generalization is not known. To address this, we used a combination of plasma endocannabinoid measurement and neuroimaging from a childhood maltreatment exposed and non-exposed mixed population combined with human and rodent fear conditioning models. Here we show that 2-AG levels are inversely associated with fear generalization at the behavioral level in both mice and humans. In mice, 2-AG depletion increases the proportion of neurons, and the similarity between neuronal representations, of threat-predictive and neutral stimuli within prelimbic prefrontal cortex ensembles. In humans, increased dorsolateral prefrontal cortical-amygdala resting state connectivity is inversely correlated with fear generalization. These data provide convergent cross-species evidence that 2-AG is a key regulator of fear generalization and suggest 2-AG deficiency could represent a trauma-related disorder susceptibility endophenotype., Competing Interests: Disclosures: Dr. Patel is a scientific consultant for Psy Therapeutics, Janssen Pharmaceuticals, and Jazz Pharmaceuticals for work unrelated to the topic of this manuscript. Dr. Heilig has received consulting fees, research support, or other compensation from Indivior, Camurus, BrainsWay, Aelis Farma, and Janssen Pharmaceuticals. Dr. Mayo is a scientific consultant for Synendos Therapeutics. The other authors report no financial relationships with commercial interests.