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Introduction: Up‐regulation of odontogenic differentiation, dentin formation, and angiogenesis in dental pulp are key factors in vital pulp therapy. The aim of this study was to investigate whether leptin could promote odontogenic differentiation and angiogenesis in human dental pulp cells (hDPCs). In addition, the involvement of the intracellular signaling pathway in these effects was determined. Methods: The viability of hDPCs treated with leptin was examined using the water soluble tetrazolium salt‐1 assay. Real‐time polymerase chain reaction was performed to determine messenger RNA (mRNA) expression levels of odontogenic and angiogenic markers. Western blot analysis was used to measure odontogenic and angiogenic protein expression levels and assess mitogen‐activated protein kinase (MAPK) pathway involvement. Alkaline phosphatase (ALP) and alizarin red staining were used to evaluate expression levels of ALP and calcified nodule formation after treatment with leptin and/or the presence of MAPK inhibitors. Results: All concentrations of leptin used in this study did not significantly affect the viability of hDPCs. However, mRNA and protein levels of odontogenic and angiogenic markers, ALP activity, and calcified nodule formation were significantly increased in the leptin‐treated group compared with those in the control group. Leptin enhanced phosphorylation of extracellular signal‐related kinases, c‐Jun N‐terminal kinase, and p38 mitogen‐activated protein kinases within 5 minutes after treatment. However, leptin‐induced dentin sialophosphoprotein and vascular endothelial growth factor protein expression and mineralization were appreciably blocked by the presence of MAPK inhibitors. Conclusions: Leptin can induce angiogenesis, odontogenic differentiation, and mineralization in hDPCs via activating the MAPK signaling pathway. HighlightsWe examined the biocompatibility and the effects of leptin on odontogenic differentiation and angiogenesis of human dental pulp cells (hDPCs).All concentrations of leptin used in this study did not affect the viability of hDPCs.Leptin treatment increased the messenger RNA and protein levels of odontogenic and angiogenic markers, alkaline phosphatase activity, and calcified nodule formation.Activation of the mitogen‐activated protein kinase signaling pathway is involved in leptin‐induced odontogenic differentiation and angiogenesis of hDPCs.