We investigated whether corticotropin‐releasing factor receptor 2 (CRF2R) and its high affinity agonist urocortin 1 (Ucn1) mediate sex‐specific signaling and immune responses using an in vivo model of inflammatory bowel disease (IBD). Male and female wild‐type (WT) and CRF2R heterozygous (CRF2R+/−) mice, immunoassays, flow cytometry, and microscopy, were used to examine sex‐specific responses. CRF2R+/− mice of both sexes were more susceptible to colitis‐induced mortality than their WT littermates. Ucn1 rescued male CRF2R+/− mice from colitis‐induced mortality, whereas it increased mortality in female CRF2R+/− mice. Ucn1 restored colon length, spleen and adrenal mass, and decreased colonic TNF‐α and IL‐1β levels to baseline levels in male CRF2+/− mice alone. Treatment with monoclonal anti‐TNF‐a ameliorated colitis‐induced inflammation in both sexes, suggesting that Ucn1 actions are upstream of TNF‐α and gender‐specific. CRF2R+/− mice of both sexes showed decreased phosphorylation of MAPK p38 and cytoprotective heat shock protein 27 (Hsp27) levels. Ucn1 restored p‐Hsp27 levels in male CRF2R+/− mice alone. Baseline expression of the chaperone protein Hsp90 was reduced in male CRF2R+/− mice to start with and did not change during colitis or after Ucn1 treatment, suggesting that CRF2R interaction with Hsp90 is critical. Expression levels and subcellular localization of CRF2R and Ucn1 in pediatric IBD patients was dysregulated and gender‐specific. To conclude, CRF2R is a key determinant of the observed sex‐specific immune and cellular signaling responses. We established that Ucn1 mediates sex‐specific responses during IBD via CRF2R, emphasizing the need for inclusion of females in preclinical studies.Support or Funding InformationNIH/NIDDK R01‐080787 to AB