Social isolation has been found to correlate with an increase in alcohol consumption in humans. However, neurobehavioral and neurocellular mechanisms underlying interactions between alcohol and social isolation have been understudied. Prior work has shown that socially isolated crayfish exhibit lower behavioral and neural sensitivity to acute ethanol (EtOH) exposure than communally-housed conspecifics. Here we report an important role of the serotonergic system in mediating this socially-dependent effect. We found that depletion of serotonin (5-HT) from serotonergic neurons reduced behavioral sensitivity to EtOH, but the effect was more pronounced in communally housed animals. In addition, antagonizing 5-HT2β receptors also reduced EtOH sensitivity, and more strongly in group-housed animals, suggesting a possible down-regulation of 5-HT2β receptors in isolates. Pre-treatment with a selective serotonin reuptake inhibitor (fluoxetine) produced opposite modulatory effects, affirming the role of 5-HT in shaping the interactions between social experience and EtOH sensitivity. Thus, we show here, for the first time, that behavioral sensitivity to acute EtOH (i.e., intoxication) in crayfish is partially mediated by 5-HT, and our results suggest specific 5-HT receptor subtypes as possible targets for these interactions. This work might have relevance for studying the neurochemical mechanisms underlying the interplay between social history and alcohol sensitivity in other organisms. However, due to large variability in the experimental data and differences in sample sizes across conditions, the results should be considered preliminary, and future work will be aimed at increasing sample sizes and replication of results.