Prognosis after myocardial infarction (MI) varies greatly depending of the extent of damaged area and the management of biological processes during recovery. Reportedly, the inhibition of the pro-inflammatory S100A9 reduces myocardial damage after MI. We hypothesize that S100A9 blockade induces changes of major signaling pathways implicated in post-MI healing. The S100A9 blocker (ABR-23890) was given for 3 days after coronary ligation. At 3- and 7-days post-MI, ventricle samples were analyzed versus control and sham-operated mice. Blockade of S100A9 modulated the expressed proteins involved in five biological processes: leu-kocyte cell-cell adhesion, regulation of muscle cell apoptotic process, regulation of intrinsic apoptotic signaling pathway, sarcomere organization and cardiac muscle hypertrophy. The blocker induced regulation of 36 proteins interacting with or targeted by the cellular tumor antigen p53, prevented myocardial compensatory hypertrophy, and reduced cardiac markers of post-ischemic stress. The blockade effect was prominent at day 7 post-MI when the quantitative features of ventricle proteome were closer to controls.