Alcohol relapse is the treatment target for medications development for alcohol dependence. Aticaprant, a selective and short-acting kappa-opioid receptor (KOR) antagonist, has recently been under development for new clinical implications (depression or anhedonia). Recent studies have also found that aticaprant reduces alcohol intake and prevents stress- triggered alcohol seeking in rodents via a KOR-mediated mechanism. Here, we further investigated whether aticaprant alone or in combination with naltrexone (muopioid receptor [MOR] antagonist) altered alcohol relapse-like drinking using a mouse alcohol deprivation effect (ADE) paradigm to mimic the relapse episodes in human alcoholics. A long-acting and selective KOR antagonist nor-BNI was used as a reference compound for the effects of the KOR antagonism on the ADE. After 3-week intermittentaccess alcohol drinking (two-bottle choice, 24-h access every other day), male and female mice displayed excessive alcohol intake and then pronounced ADE after 1-week abstinence. Aticaprant alone decreased alcohol ADE in a dose- dependent manner (1-3 mg/kg) in both males and females. Aticaprant at a lower dose (0.3 mg/kg) than the effective one (3 mg/kg) combined with a low dose of naltrexone (1 mg/kg) reduced the ADE in both sexes, and the combination was effective after a multi-dosing regimen (5 daily injections during the abstinence) without development of tolerance, suggesting synergistic effects of the combination. In contrast, nor-BNI alone or with naltrexone had no effect on the ADE in either sex. Our present study suggests that a combination of clinically developed, short-acting KOR antagonist aticaprant with low-dose naltrexone has therapeutic potential in alcohol “relapse” treatment.