The endocannabinoid system plays an important role in multiple behavioral responses due to its wide distribution in the central nervous system. The cannabinoid CB1 receptor was associated to the loss of behavioral control over food intake occurring during food addiction. The cannabinoid CB2 receptor (CB2R) is expressed in brain areas canonically associated with addictive-like behavior and was linked to drug-addictive properties. In this study, we evaluated for the first time the specific role of the CB2R in food addiction by using a well-validated operant mouse model of long-term training to obtain highly palatable food. We have compared in this model the behavioral responses of wild-type mice, mutant mice constitutively lacking CB2R, and transgenic mice overexpressing CB2R. The lack of CB2R constitutes a protective factor for the development of food addiction and the impulsive and depressive-like behavior associated. In contrast, the overexpression of CB2R induces a vulnerable phenotype toward food addiction after long-term exposure to highly palatable chocolate pellets. Relevant transcriptomic changes were associated to resilience and vulnerability to food addiction depending on the genotype, which provides a mechanistic explanation for these behavioral changes. Therefore, CB2R may constitute a potential therapeutic target for the loss of eating control and the comorbid emotional effects associated to food addiction. Display omitted •The lack of CB2R constitutes a protective factor for impulsivity- and compulsivity-like behavior associated with food addiction.•Overexpression of CB2R induces a vulnerable phenotype toward food addiction.•The lack of CB2R was associated with increased cnr1 expression in the NAc and decreased crf expression in the PVN.•Overexpression of CB2R decreased the expression of Cnr1 and Oprm1 in the NAc, th in the VTA, drd1 in the IL and increased crf expression in the PVN.