Methylglyoxal (MG) production after myocardial infarction (MI) leads to advanced glycation end-product formation, adverse remodeling, and loss of cardiac function. The extracellular matrix (ECM) is a main target for MG glycation. This suggests that ECM-mimicking biomaterial therapies may protect the post-MI environment by removing MG. In this study, mechanisms by which a recombinant human collagen type I hydrogel therapy confers cardioprotection are investigated. One-week post-MI, mice receive intramyocardial injection of hydrogel or PBS. The hydrogel improves border zone contractility after 2 days, which is maintained for 28 days. RNA sequencing shows that hydrogel treatment decreases the expression of erythroid differentiation regulator 1, a factor associated with apoptosis. Hydrogel treatment reduces cardiomyocyte apoptosis and oxidative stress at 2 days with greater myocardial salvage seen at 28 days. The hydrogel located at the epicardial surface is modified by MG, and less MG-modified proteins are observed in the underlying myocardium of hydrogel-treated mice. Biomaterials that can be a target for MG glycation may act as a sponge to remove MG from the myocardium post-MI. This leads to less oxidative stress, greater survival and contractility of cardiomyocytes, which altogether suggests a novel mechanism by which biomaterials improve function of the infarcted heart.