The serine hydrolase α/β-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1−/− or Cnr2−/− mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABAA receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntington’s disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its antiepileptic activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel antiepileptic strategy. •ABHD6 blockade by WWL123 controls PTZ-induced seizures without psychomotor effects•The effect of WWL123is retained in Cnr1−/− and Cnr2−/− mice but blocked by picrotoxin•WWL123 also blocks spontaneous seizures in the R6/2 mouse model of juvenile HD•R6/2 hippocampi feature electrographic abnormalities and profound loss of NPY Cannabinoids reduce seizure incidence but also induce psychotropic side effects. Here Naydenov and Horne et al. show that seizure incidence is controlled by inhibition of ABHD6, a novel endocannabinoid-degrading enzyme, without producing psychotropic side effects.