Background and Purpose Stress is a major risk factor for psychiatric disorders and significantly affects neuroplasticity in brain areas including the nucleus accumbens (NAc) and the insular cortex (IC). Here, we examined alterations in neuroplasticity within the aIC-NAc circuit following restraint stress in male and female rats, and determined the involvement of the endocannabinoid system in this response. Experimental Approach We subjected male and female rats to a 2h-period of acute restraint stress. Following this, we performed behavioral experiments, c-Fos immunohistochemistry and in vivo electrophysiological recordings of NAc neurons in response to aIC stimulation from anesthetized male and female rats immediately and 24h after stress exposure. Since the effect of stress was observed only in males, we evaluated the effects of blockade of cannabinoid CB1 receptors in male rats. Key Results We show that synaptic plasticity in the aIC-NAcC pathway differs between male and female rats. Under basal conditions, in males, long-term potentiation and long-term depression were equally induced, whereas in females, we found mostly a long-term potentiation. Moreover, stress affected synaptic plasticity in the aIC-NAcC only in males, inducing a loss of long-term-depression 24h after stress. Finally, blocking CB1 receptors in males restored long-term depression. Conclusion and Implications These results demonstrate that integration of aIC information to NAcC differs between males and females, that stress affects neuroplasticity only in males, an effect that depends on the endocannabinoid system. This study provides mechanistic support for differential reactivity to stress between males and females that may relate to stress-related psychiatric disorders.