Fermented mare’s milk (koumiss), a traditional Central Asian dairy product derived from fermented mare’s milk, is renowned for its unique sour taste and texture. It has long been consumed by nomadic tribes for its nutritional and medicinal benefits. This study aimed to comprehensively analyze the protective effects of koumiss against alcohol-induced harm across behavioral, hematological, gastrointestinal, hepatic, and reproductive dimensions using a mouse model. Optimal intoxicating doses of alcohol and koumiss doses were determined, and their effects were explored through sleep tests and blood indicator measurements. Pretreatment with koumiss delayed inebriation, accelerated sobering, and reduced mortality in mice, mitigating alcohol’s impact on blood ethanol levels and various physiological parameters. Histopathological and molecular analyses further confirmed koumiss’s protective role against alcohol-induced damage in the liver, stomach, small intestine, and reproductive system. Transcriptomic studies on reproductive damage indicated that koumiss exerts its benefits by influencing mitochondrial and ribosomal functions and also shows promise in mitigating alcohol’s effects on the reproductive system. In summary, koumiss emerges as a potential natural agent for protection against alcohol-induced harm, opening avenues for future research in this field.