Sexual dimorphism is an important factor in understanding various diseases, including inflammatory bowel disease (IBD). While females typically exhibit stronger immune responses, the role of sex in IBD remains unclear. This study aimed to explore the sex-dependent differences and inflammatory susceptibility in the most extensively used IBD mouse model as they developed colitis. We monitored IL10-deficient mice (IL-10−/−) up to 17 weeks of age and characterized their colonic and fecal inflammatory phenotype, as well as their microbiota changes. Here, we originally identified IL-10−/−female mice as more prone to developing intestinal inflammation, with an increase in fecal miR-21, and dysbiosis with more detrimental characteristics compared to males. Our findings provide valuable insights into the sex-based differences in the pathophysiology of colitis and emphasize the importance of considering sex in experimental designs. Moreover, this study paves the way for future investigations aiming at addressing sex-related differences for the development of adequate disease models and therapeutic strategies, ideally enabling personalized medicine.