Cannabinoid receptors have been examined as potential targets to alleviate the negative consequences of anxiety, trauma-related, and stress-related disorders. However, in preclinical animal studies, synthetic cannabinoids can produce adverse motoric and cognitive effects. Thus, pharmacological strategies that augment endocannabinoid levels in the brain, with the aim of enhancing signaling through cannabinoid receptors, are being investigated for their ability to modulate anxiety and stress responses. Previously, we have demonstrated that either genetic removal of prostaglandin-endoperoxide synthase 2 gene, which codes for the cyclooxygenase-2 (COX-2) enzyme that degrades the endocannabinoids, anandamide and 2-arachidonylglycerol, or pharmacologically inhibiting COX-2 activity with a substrate-selective COX-2 inhibitor (SSCI), LM-4131, can increase brain anandamide levels. These elevations in endocannabinoid levels in the rodent brain resulted in enhanced endocannabinoid signaling through the cannabinoid type 1 receptor and, subsequently, reduced anxiety-like behaviors in mice under basal conditions. Using the novelty-induced feeding suppression assay, elevated plus maze, and in vivo electrophysiology, we tested the hypothesis that endocannabinoid augmentation via SSCIs may have the potential to counteract stress-induced anxiety-like behaviors. We have found that the SSCIs, LM-4131 and lumiracoxib, and the selective COX-2 inhibitor, celecoxib, can reduce anxiety-like behaviors in mice subjected to footshock stress. In contrast, these inhibitors had little effect in non-stressed mice. The anxiolytic action of the SSCI, LM-4131, was mediated through the cannabinoid type 1 receptor under non-stressed (control) conditions, but mediated through the small conductance calcium-activated potassium (SK) channels when mice were subjected to footshock stress. Also, we have found that the anxiolytic effects of SSCIs in stressed mice may be due to a decrease in excitatory cell firing in the amygdala.