Background and PurposeCytoplasmic fragile X messenger ribonucleoprotein 1 (FMR1)‐interacting protein 2 (CYFIP2), as a component of the Wiskott–Aldrich syndrome protein family verprolin‐homologous protein (WAVE) regulatory complex, is involved in actin polymerization, contributing to neuronal development and structural plasticity. Mutating serine‐968 to phenylalanine (S968F) in CYFIP2 causes an altered cocaine response in mice. The neuronal mechanisms underlying this response remain unknown.Experimental ApproachWe performed cocaine reward‐related behavioural tests and examined changes in synaptic protein phenotypes and neuronal morphology in the nucleus accumbens (NAc), using CYFIP2 S968F knock‐in mice to investigate the role of CYFIP2 in regulating cocaine reward.Key ResultsCYFIP2 S968F mutation attenuated cocaine‐induced behavioural sensitization and conditioned place preference. Cocaine‐induced c‐Fos was not observed in the NAc of CYFIP2 S968F knock‐in mice. However, c‐Fos induction was still evident in the medial prefrontal cortex (mPFC). CYFIP2 S968F mutation altered cocaine‐associated CYFIP2 signalling, glutamatergic protein expression and synaptic density in the NAc following cocaine exposure. To further determine the role of CYFIP2 in NAc neuronal activity and the mPFC projecting to the NAc activity‐mediating reward response, we used optogenetic tools to stimulate the NAc or mPFC‐NAc pathway and observed that optogenetic activation of the NAc or mPFC‐NAc pathway induced reward‐related behaviours. This effect was not observed in the S968F mutation in CYFIP2.Conclusion and ImplicationsThese results suggest that CYFIP2 plays a role in controlling cocaine‐mediated neuronal function and structural plasticity in the NAc, and that CYFIP2 could serve as a target for regulating cocaine reward.