Chronic Chagas cardiomyopathy (CCC) is a severe complication of Chagas disease caused by the parasite Trypanosoma. cruzi, endemic to Latin America and affecting over 7 million people, with an additional 65 million individuals at risk. The acute phase of infection is usually asymptomatic, but if untreated, it can progress to a chronic phase, leading to cardiac or digestive complications. The persistence of the parasite leads to the production of pro-inflammatory cytokines and activation of the innate immune system, triggered by recognizing pathogen-associated molecular patterns and releasing damage-associated molecular patterns (DAMPs) from host cells in response to infections and other pathological processes. This study investigated the role of high mobility group box 1 (HMGB1) and its receptor, the receptor for advanced glycation end products (RAGE), in the inflammation induced by T. cruzi in infected EA. hy926 endothelial cells and in chronically infected mice. EA. hy926 cells secrete HMGB1 in response to parasite infection, leading to increased expression of RAGE, and the FPS-zM1 inhibitor modulates TNF-alpha secretion. In the murine CCC model, both HMGB1 and RAGE exhibited increased expression in the endothelial cells of infected mice. Blocking RAGE partially reduced fibrosis and the inflammatory infiltrate while modulating levels of IFN gamma and TNF alpha. This study provides the first evidence supporting the involvement of host DAMPs in the inflammatory response associated with CCC.