Periodontitis causes inflammatory destructions of tooth-supporting tissue and constitutes a significant burden on public health. Failing to reserve the tissue damage and bone loss by any of the currently available therapies has left periodontitis uncurable thus far. Understanding the molecular mechanism in the inflammatory process is crucial to elucidating the pathogenesis and enlightening new therapeutic strategies for periodontitis. This study was to investigate whether and how ferroptosis, a newly-discovered form of cell death, was involved in the pathogenesis of periodontitis. Healthy and periodontitis human gingiva samples were collected and ligature-induced periodontitis murine models were constructed to investigate the role of ferroptosis in periodontitis. Single-cell RNA sequencing data was analyzed to identify the cell type that underwent ferroptosis. The susceptibility of human gingival fibroblasts to ferroptosis was investigated by in vitro cell cultures. We found that gingival fibroblasts undergo ferroptosis in periodontitis, and that periodontitis-induced tissue damage and bone loss were alleviated by inhibition of ferroptosis. Periodontitis-induced pro-inflammatory immune responses was featured by profound elevation of fibroblast-derived Interleukin-6, which was attenuated by ferroptosis inhibition. These results indicated fibroblast ferroptosis as a new clue to unveiling the cellular and molecular basis for periodontitis-induced tissue damage. Involvement of ferroptosis/Interleukin-6 signaling in the pathogenic process suggested a potential target for immunopharmacological approaches to curing periodontitis.