Amelogenin is a complex enamel matrix protein that consists of various molecular-size proteins and amino acids. A spliced form of amelogenin was identified that included exons 2, 3, 5, 6, and 7. However, the biological function of amelogenin exon 5 on dental pulp remains unknown. We designed a synthetic amelogenin exon 5 encoded peptide (SP), which was based on a protein produced by cells in response to the enamel matrix derivative (EMD). We investigated the effect of the SP on potentiation of osteogenesis and its signal pathway in dental pulp stem cells (DPSCs). DPSCs are an important cell for pulp tissue homeostasis. DPSCs were cultured with SP to examine the effect of cell proliferation and osteogenic differentiation. We also investigated the mitogen-activated protein kinase (MAPK) signaling pathway. SP significantly enhanced cell proliferation and the expression of osteogenic differentiation. Moreover, SP promoted the expression of the MAPK signaling pathway. Therefore, amelogenin exon 5 might contribute to dental pulp capping.