Following a myocardial infarction, lymphocytes have been suggested to react with the damaged heart tissue, which can impair proper tissue healing. In the present work, we investigate whether ingestion of a myocardial homogenate and the consequent development of immunological tolerance can modify the course of post-infarction myocardial repair. Infarction-like myocardial lesions were induced in Wistar rats by injecting high doses of isoproterenol. The healing process was evaluated morphologically and functionally for 60 days. Cardiac function was evaluated using isolated and perfused heart (Langendorff) preparations. At day 14 after isoproterenol treatment, lymphocytes from the mediastinal lymph nodes proliferated when exposed in vitro to myocardial homogenate. Moreover, TNF-α, IFN-γ and CCL-5, but not FOXP3⁺ expression, was increased in draining lymph nodes in isoproterenol-injured animals, indicating that the observed lymphocyte population that proliferated in response to cardiac components presented a pro-inflammatory and pro-fibrotic profile. In contrast, lymphocytes from draining lymph nodes of rats given a heart homogenate by gavage 7 days before isoproterenol did not proliferate. Furthermore, the group rendered tolerant expressed cardiac FOXP3⁺ earlier than did the control group, and showed a milder inflammatory infiltrate, lower MMP-9 expression, less collagen deposition, and improved cardiac performance when compared to animals that received only isoproterenol administration. The present findings suggest that the establishment of oral tolerance to heart components prior to myocardial infarction may drive the cardiac healing process to proceed with less inflammation and fibrosis, thus preserving contractile organ function.