Periostin is an extracellular matrix protein from fasciclin family, and it plays an important role in the cell adhesion, migration, and growth of the organism. Periostin prevents apoptosis while stimulating cardiomyocytes. The present study was designed to investigate cardioprotective effects of the recombinant murine periostin peptide administration in a rat model of isoproterenol (ISO)-induced myocardial injury. The experiment was performed on 84 adult male Sprague Dawley rats in 4 groups (n = 21): control group (1), periostin-treated group (2), ISO-treated group (3), and ISO + periostin-treated group (4). The groups were further divided into three subgroups based on the duration of the experiment in which rats were killed on days 1, 7, and 28 (n = 7). Growth factors (VEGF, ANGPT, FGF-2, TGF beta), mitosis and apoptosis (Bcl-2, Bax, PCNA, Ki-67, phospho-histone H3), cell cycle activators and inhibitors (cyclin D1, D2, A2, Cdc2), the origin of regenerating cells (cKit and CD45) mRNA were detected using quantitative real-time polymerase chain reaction (PCR) and PCR array. Immunohistochemistry staining was used to directly detect protein level and distribution in the heart tissues. Administration of periostin following ISO-induced cardiotoxicity revealed that periostin alleviated deleterious effects of ISO through several pathways: (1) periostin induced mitotic activity of endothelial/fibroblastic cells, (2) periostin drives cardiomyocytes into S and M phases, thus promoting proliferation of cardiomyocytes, (3) periostin contributed to collagen degradation, tissue remodeling, and reduced cardiac fibrosis during the healing process following myocardial damage while preserving tissue matrix, (4) periostin stimulated angiogenesis by upregulating THBS1, TGFB2, and HGF genes, (5) periostin regulated cell growth and proliferation while maintaining cell shape and cellular muscle contractions (ACTB) and functioned as chemoattractant factor (CCL2) at the beginning of myocardial damage.