Actin dynamics in dendritic spines can be associated with the neurobiological mechanisms supporting the comorbidity between stress exposure and cocaine increase rewards. The actin cytoskeleton remodeling in the nucleus accumbens (NA) has been implicated in the expression of stress-induced cross-sensitization with cocaine. The main of the present study is evaluate the involvement of cofilin, a direct regulator of actin dynamics, in the impact of stress on vulnerability to cocaine addiction. Here, we show that the inhibition of cofilin expression in the NA core using viral short-hairpin RNA is sufficient to prevent the cocaine sensitization induced by chronic stress. Moreover, the reduced cofilin levels also impede a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor surface expression enhancement and promote the reduction of head diameter of spines in animals pre-exposed to stress after a cocaine challenge in the NA core. We report that cofilin downregulation prevents facilitation of the acquisition of cocaine self-administration (SA) in male rats pre-exposed to chronic stress. These findings highlight the role of cofilin in the neurobiological mechanisms supporting the comorbidity between stress exposure and addiction-related disorders.