Objective Stem cells from human exfoliated deciduous teeth (SHED) are a unique postnatal stem cell population capable of regenerating mineralized tissue and treating immune disorders. However, the mechanism that controls SHED differentiation is not fully understood. Here, we showed that basic fibroblast growth factor (bFGF) treatment attenuated SHED-mediated mineralized tissue regeneration through activation of the extracellular signal-regulated kinase (ERK) 1/2 pathway. Material and Method The level of mineralized nodule formation was assessed by alizarin red staining. Expression levels of osteogenic genes, OCN and Runx2, were examined by RT-PCR. Subcutaneous implantation approach was used to assess in vivo bone formation. Downstream signaling pathways of bFGF were examined by Western blotting. Result Activation of ERK1/2 signaling by bFGF treatment inhibited WNT/β-catenin pathway, leading to osteogenic deficiency of SHED. ERK1/2 inhibitor treatment rescued bFGF-induced osteogenic differentiation deficiency. Conclusion These data suggest that bFGF inhibits osteogenic differentiation of SHED via ERK1/2 pathway. Blockade ERK1/2 signaling by small molecular inhibitor-treatment improves bone formation of SHED after bFGF treatment.