Investigation on the effect of Piezo1 on periodontal tissue and periodontal ligament fibroblasts (PDLFs) under mechanical stress and the underlying mechanism. The orthodontic tooth movement rat model was established via an orthodontic spiral tension spring. PDLFs were cultured and subjected to 2.0 g/cm2 static compressive loading. Blocked the Piezo1 via Piezo1 inhibitor, GsMTx4. TUNEL staining and flow cytometry determined the apoptosis rate of periodontal tissue and PDLFs in rats. Expression of Piezo1, p‐p38 and ERK1/2 was analysed by immunofluorescence assay and western blotting. Piezo1 inhibitor GsMTx4 relieved the increased expression of Piezo1, ERK1/2 and p‐p38, and alleviated apoptosis in periodontal tissue and PDLFs under compressive loading. Piezo1 inhibition can alleviate force‐induced apoptosis and damage in rats' periodontal tissue and PDLFs, and regulate the p38/ERK1/2 signalling pathway.