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Circadian genes in the medial accumbal shell (mNAcSh) region regulate binge alcohol consumption. Here, we investigated if antisense‐induced knockdown of major circadian genes (Per1, Per2, and NPAS2) in the mNAcSh of mice exposed to intermittent access two‐bottle choice (IA2BC) paradigm modulates the expression of histone deacetylase‐2 (HDAC‐2) and CREB‐binding protein (CBP), key epigenetic modifiers associated with withdrawal‐associated behaviors such as anxiety. Adult male C57BL/6J mice (N = 28), surgically implanted with bilateral guide cannulas above the mNAcSh, were chronically (4 weeks) exposed to alcohol (20% v/v) or saccharin (0.03%) via IA2BC paradigm. In the fourth week, a mixture of antisense (AS‐ODNs; N = 14/group) or nonsense (NS‐ODNs; N = 14/group) oligodeoxynucleotides against circadian genes were bilaterally infused into the mNAcSh. Subsequently, alcohol/saccharin consumption and preference were measured followed by euthanization of animals and verification of microinjection sites by visual inspection and the expression of HDAC‐2 and CBP by using RT‐PCR along with the verification of antisense‐induced downregulation of circadian genes in the mNAcSh. As compared with NS‐ODNs, AS‐ODNs infusion significantly attenuated the alcohol‐induced increase in HDAC‐2 and reduction in CBP expression in the mNAcSh along with a significant reduction in alcohol consumption and preference. No significant effect was observed on either saccharin consumption or preference. Our results suggest that circadian genes in the mNAcSh may have a causal to play in mediating epigenetic changes observed after chronic alcohol consumption. [ABSTRACT FROM AUTHOR]