Individuals suffering from substance-use disorders develop strong associations between the drug’s rewarding effects and environmental cues, creating powerful, enduring triggers for relapse. We found that dephosphorylated, nuclear histone deacetylase 5 (HDAC5) in the nucleus accumbens (NAc) reduced cocaine reward-context associations and relapse-like behaviors in a cocaine self-administration model. We also discovered that HDAC5 associates with an activity-sensitive enhancer of the Npas4 gene and negatively regulates NPAS4 expression. Exposure to cocaine and the test chamber induced rapid and transient NPAS4 expression in a small subpopulation of FOS-positive neurons in the NAc. Conditional deletion of Npas4 in the NAc significantly reduced cocaine conditioned place preference and delayed learning of the drug-reinforced action during cocaine self-administration, without affecting cue-induced reinstatement of drug seeking. These data suggest that HDAC5 and NPAS4 in the NAc are critically involved in reward-relevant learning and memory processes and that nuclear HDAC5 limits reinstatement of drug seeking independent of NPAS4. •Nuclear HDAC5 in the NAc attenuates relapse-like drug-seeking behaviors•ChIP-seq revealed numerous HDAC5-associated target genes including Npas4•NPAS4 in NAc is induced in subset of FOS+ neurons during cocaine-context learning•HDAC5 and NPAS4 in NAc are involved in cocaine-conditioned behaviors Taniguchi and colleagues find that the epigenetic enzyme, histone deacetylase 5 (HDAC5), reduces relapse-like behaviors in a model of cocaine addiction and that HDAC5 and its target gene, Npas4, are important in the nucleus accumbens for reward-related learning processes.