<p>Electroencephalographic (EEG) recordings in individuals with Fragile X Syndrome (FXS) and the mouse model of FXS (<i>Fmr1</i> KO) display cortical hyperexcitability at rest, as well as deficits in sensory-driven cortical network synchrony. A form of circuit hyperexcitability is observed in ex vivo cortical slices of <i>Fmr1</i> KO mice as prolonged persistent activity, or Up, states. It is unknown if the circuit mechanisms that cause prolonged Up states contribute to FXS-relevant EEG phenotypes. Here we examined the role of endocannabinoids (eCB) in prolonged Up states in slices and resting and sensory-driven EEG phenotypes in awake <i>Fmr1</i> KO mice. Bidirectional changes in eCB function are reported in the <i>Fmr1</i> KO that depend on synapse type (excitatory or inhibitory). We demonstrate that pharmacological or genetic reduction of Cannabinoid Receptor 1 (CB1R) in GABAergic neurons rescues prolonged cortical Up states and deficits in sensory-driven cortical synchrony in <i>Fmr1</i> KO mice. In support of these findings, recordings from <i>Fmr1</i> KO cortical Layer (L) 2/3 pyramidal neurons revealed enhanced CB1R-mediated suppression of inhibitory synaptic currents. In contrast, genetic reduction of <i>Cnr1</i> in glutamatergic neurons did not affect Up state duration, but deletion of <i>Fmr1</i> in the same neurons was sufficient to cause long Up states. These findings support a model where loss of <i>Fmr1</i> in glutamatergic neurons leads to enhanced CB1R-mediated suppression of GABAergic synaptic transmission, prolonged cortical circuit activation and reduced sensory-driven circuit synchronization. Results suggest that antagonism of CB1Rs may be a therapeutic strategy to correct sensory processing deficits in FXS.</p>