Periodontitis is an inflammatory condition that affects the tooth‐supporting structures, triggered by the host's immune response toward the bacterial deposits around the teeth. Annexin A1 (AnxA1), a vital member of the annexin superfamily, is known for its diverse physiological functions, particularly its anti‐inflammatory and anti‐senescence properties. We hypothesized that AnxA1 has a protective effect against lipopolysaccharide (LPS)‐induced inflammatory responses and cellular damage in periodontal ligament cells (PDLCs). In this study, we demonstrate that LPS stimulation significantly reduced telomerase activity in PDLCs, a decline that was dose‐dependently reversed by AnxA1. Importantly, AnxA1 protected the cells from LPS‐induced cellular senescence and the downregulation of human telomerase reverse transcriptase (hTERT) expression. In line with this, AnxA1 suppressed the LPS‐induced expression of p21 and p16 at both the mRNA and protein levels. Furthermore, AnxA1 demonstrated potent anti‐inflammatory effects by inhibiting the secretion of interleukin 6 (IL‐6), interleukin 8 (IL‐8), and monocyte chemoattractant protein‐1 (MCP‐1). It also mitigated LPS‐induced oxidative stress by reducing the levels of phosphorylated Foxo3a (Ser253) and restored sirtuin 1 (SIRT1) expression. Notably, SIRT1 silencing abolished AnxA1's protective effects on Foxo3a phosphorylation and cellular senescence, suggesting that SIRT1 mediates AnxA1's actions. In conclusion, AnxA1 protected PDLCs against LPS‐triggered inflammation and cell senescence by activating SIRT1 signal pathway. These findings indicate that AnxA1 could serve as a promising therapeutic strategy for the treatment of periodontitis.