AbstractFibroblast growth factor‐2 (FGF‐2) stimulates periodontal regeneration by a broad spectrum of effects on periodontal ligament (PDL) cells, such as proliferation, migration, and production of extracellular matrix. A critical factor in the success of periodontal regeneration is the rapid resolution of inflammatory responses in the tissue. We explored an anti‐inflammatory effect of FGF‐2 during periodontal regeneration and healing. We found that FGF‐2 on mouse periodontal ligament cells (MPDL22) markedly downregulated CD40 expression, a key player of inflammation. In addition, FGF‐2 inhibited CD40 signaling by the non‐canonical nuclear factor‐kappa B2 (NFκB2) pathway, resulting in decreased production of interleukin‐6 (IL‐6) and tumor necrosis factor‐α (TNF‐α), which have the potential to recruit immune cells to inflamed sites. Furthermore, in vivo treatment of FGF‐2 enhanced healing of skin wounds by counteracting the CD40‐mediated inflammation. These results reveal that FGF‐2 has an important function as a negative regulator of inflammation during periodontal regeneration and healing.