Cardiac hypertrophy is a compensatory response to pathological stimuli. Recent studies have suggested that calcium-sensing receptor (CaSR) plays an important role in the development of cardiac hypertrophy. Ginsenoside Re (Re) is a monoconstituent of the ginseng plant. Many studies have shown that Re has various beneficial pharmacological effects on the cardiovascular system. It remains uncertain if Re have an anti-cardiac hypertrophic effect through the modulation of the CaSR-mediated signaling pathway. In this research, we employed a rat model of cardiac hypertrophy to investigate the relationship between Re and CaSR. Significant reductions in blood pressure, left ventricle hypertrophic indexes, cross-sectional area of cardiomyocytes, and levels of the β-myosin heavy chain and atrial natriuretic peptide were observed in spontaneously hypertensive rats (SHR) after Re administration. In addition, Re improved cardiac structure and function in SHR. Furthermore, Re inhibited CaSR, calcineurin (CaN), nuclear factor of activated T cells 3 (NFAT3), phosphorylated zinc finger transcription factor 4 (p-GATA4), protein kinase C-β (PKC-β), rapidly accelerated fibrosarcoma-1 (Raf-1), and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2). It also increased the expression of p-NFAT3 and mitogen-activated protein kinase phosphatase-1 (MKP-1). These findings suggest that Re has beneficial effects on cardiac hypertrophy in SHR. The mechanisms underlying these effects are the regulation of the PKC-MAPK axis and the CaSR-mediated signaling pathway.