Celiac disease is a gluten-driven inflammatory disorder of the small intestine in which HLA-DQ2- or HLA-DQ8–restricted presentation of deamidated gluten peptides activates pathogenic CD4+ T cells. Although transglutaminase 2 (TG2) is a central autoantigen and catalyst in celiac disease, whether chronic extracellular TG2 activation is sufficient to drive intestinal pathology in vivo remains unclear. Here, we generated a germline TG2 C230S mouse model that constitutively biases TG2 toward an open, catalytically active conformation under extracellular calcium conditions, and crossed it with HLA-DQ2 transgenic mice. Using the activity-based probe HB-230, we found that C230S mice exhibited increased extracellular active TG2 in the small intestine and enhanced uptake of HB-230 by CD103+ dendritic cells. Upon enhanced gluten feeding, C230S.DQ2 mice developed marked HLA-DQ2-dependent villous atrophy, elevated anti-TG2 and anti-deamidated gliadin antibody responses, and increased intestinal TG2 activity, whereas C230S or DQ2 single-mutant mice did not. Depletion of CD4+ T cells rescued tissue damage and reduced serological responses, demonstrating that gluten-reactive CD4+ T cells are required for disease manifestation. Moreover, both a gluten-free diet and pharmacologic TG2 inhibition with HB-225 reversed intestinal TG2 activation, villous atrophy, and antibody production. These findings demonstrate that continuous TG2 activation, together with gluten and HLA-DQ2, causes celiac-like enteropathy, highlighting TG2 as a promising therapeutic target.