Aim To obtain the differential microRNA expression profiles of exosomes derived from hypertrophic cardiomyocytes and normal cardiomyocytes. Further, target genes and signaling pathways were analyzed to explore the possible molecular mechanism of the differentially expressed microRNA involved in cardiac hypertrophy. Methods Primary culture of cardiac myocytes was prepared from three-day-old Wistar rats. The cells were then divided into two groups:model group and control group. In the model group, cardiomyocyte hypertrophy was induced by AngⅡ (1 μmol/L), whereas the cells in the control group were not given any treatment or only added culture medium. Additionally, the exosomes were isolated, and the differentially expressed microRNA of exosomes were obtained by microRNA sequencing technique. Furthermore, target genes of differentially expressed microRNA were identified by miRanda algorithm, and KEGG pathway analysis were carried out to identify significant biological processes and key gene/protein. Results Compared with the control group, 14 differentially expressed microRNA of exosomes in the model group were identified. Among 14 differentially expressed microRNA, 13 were up-regulated (including mmu-miR-2137, mmu-miR-5126, mmu-miR-690 and 10 were newly discovered microRNAs), and 1 were down-regulated (P<0.05). In addition, 54 target genes of differentially expressed microRNAs were obtained, and then local network diagrams were constructed using the target genes of the first 20 and their related microRNA. KEGG pathway analysis indicated that the differentially expressed microRNAs was involved in the regulation of several signaling pathways, including MAPK, PI3K-Akt, and Wnt pathways. Conclusion The microRNA expression profiles of exosomes derived from hypertrophic cardiomyocytes changed significantly. They regulated several signaling pathways through target genes, and further affected the pathophysiological process of cardiac hypertrophy.