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Introduction: This study aimed to investigate the effect of Stat3 on the osteoblast‐mediated bone healing in the inflammatory lesion. Methods: The conditional knockout of Stat3 in osteoblasts (Stat3 CKO) was generated via the Cre‐loxP recombination system using Osterix‐Cre transgenic mice. The calvarial bone inflammatory lesions were established on both Stat3 CKO and wild‐type mice, then harvested to assess the bone healing. In response to lipopolysaccharide (LPS) stimulation, osteoblasts from Stat3 CKO and wild‐type mice were subjected to examine the formation of calcium deposits, the expression of osteogenic markers (i.e., Runx2, OPN, COL1A1), and osteoclast‐related markers (i.e., RANKL, OPG). The EdU and transwell assays were performed to assess the proliferation and migration of the cells. Results: A decrease in bone mass and an increase in osteolysis were found in the inflammatory lesions on Stat3 CKO mice when compared with the control. More osteoclastic‐like cells and an increased expression of RANKL were observed in Stat3 CKO mice. Both mRNA and protein expressions of Stat3 and osteogenic markers in the lesions were significantly decreased in Stat3 CKO mice. After co‐cultured with osteogenic medium, the Stat3‐deficient osteoblasts were found with a significant decrease in calcium deposits and the expression of osteogenic markers, and with a significant increased expression of RANKL. The impaired ossification of Stat3‐deficient osteoblasts was even more pronounced with the presence of lipopolysaccharides in vitro. The most decrease in cell proliferation and migration was found in Stat3‐deficient osteoblasts in response to LPS. Conclusions: Loss of Stat3 in osteoblasts impaired bone healing in an inflammatory microenvironment. [ABSTRACT FROM AUTHOR]