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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 in a childhood maltreatment\u2013exposed and \u2013nonexposed mixed population, combined with human and rodent fear-conditioning models. Here we show that 2-AG levels were inversely associated with fear generalization at the behavioral level in both mice and humans. In mice, 2-AG depletion increased the proportion of neurons that respond to, and the similarity of neuronal representations for, both threat-predictive and neutral stimuli within prelimbic prefrontal cortex neuronal ensembles. In humans, increased dorsolateral prefrontal cortical\u2013amygdala resting-state connectivity was inversely correlated with fear generalization. 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