Anterior gradient 2 (
AGR
2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (
ER
). Mouse
AGR
2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (
IBD
). Although these biological effects are well established, the underlying molecular mechanisms of
AGR
2 function toward inflammation remain poorly defined. Here, using a protein–protein interaction screen to identify cellular regulators of
AGR
2 dimerization, we unveiled specific enhancers, including
TMED
2, and inhibitors of
AGR
2 dimerization, that control
AGR
2 functions. We demonstrate that modulation of
AGR
2 dimer formation, whether enhancing or inhibiting the process, yields pro‐inflammatory phenotypes, through either autophagy‐dependent processes or secretion of
AGR
2, respectively. We also demonstrate that in
IBD
and specifically in Crohn's disease, the levels of
AGR
2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that
AGR
2 dimers act as sensors of
ER
homeostasis which are disrupted upon
ER
stress and promote the secretion of
AGR
2 monomers. The latter might represent systemic alarm signals for pro‐inflammatory responses.