Lithium is an activator of β-catenin signaling, and β-catenin mediates bone acquisition in response to mechanical loading in the bone. We tested the hypothesis that lithium enhances new bone formation during midpalatal suture expansion. Forty-eight Wistar rats with or without suture expansion were gavage-fed daily with lithium chloride or sodium chloride. We labeled the rats with bromodeoxyuridine to evaluate the proliferation and differentiation of the osteoprogenitors. Lithium increased β-catenin expression and cell proliferation in expanding sutures. Initial delay in the differentiation of osteoprogenitors into mature osteoblasts by lithium treatment corresponded with expansion of pre-osteoblasts, which preceded the increase of new bone formation in the suture. These results suggested that β-catenin regulates proliferation of osteoprogenitors and maturation of osteoblasts during midpalatal suture expansion osteogenesis, and that lithium enhances bone regeneration by elevating β-catenin expression. Lithium treatment could be a pharmaceutical aid to improve the stability of orthodontic treatment like rapid palatal expansion.