Abstract: Objective To explore the effect of silent mating type information regulation 2 homolog 1 (SIRT1) on tunicamycin-induced endoplasmic reticulum stress (ERS) in chondrocytes. Methods After isolation of human normal chondrocytes and osteoarthritis (OA) chondrocytes, morphological identification was performed, collagen type II expression was determined by immunohistochemical staining and SIRT1 expression was detected by Western blot. Cultured chondrocytes were divided into five groups: control group (OA chondrocytes, normal chondrocytes), normal chondrocytes group (Tuni, SIRT1 overexpression, and Tuni + SIRT1 overexpression). After 24 h treatment, the expression of ERS-related proteins of C/EBP homologous protein (CHOP), eukaryotic initiation factor-2 α (eIF2α) phosphorylation, and activating transcription factor 4 (ATF4), and the expression of apoptosis-related proteins of Bcl-2, Bax, and Caspase-3, as well as p-p38 protein were determined by Western blot. NF-κB activity was determined by ELISA. Results Compared to human normal chondrocytes, both the cell proliferation and the expression of collagen type II and SIRT1 in OA chondrocytes were markedly reduced (P<0.05). OA control group and 0.5 mg/L tunicamycin treatment consistently resulted in ERS and cell apoptosis with concomitant enhancement of CHOP, p-eIF2α and ATF4 proteins, increases of NF-κB activity and p-p38, Bax, Caspase-3 proteins, and reduction of Bcl-2 (P<0.05). However, SIRT1 overexpression could reverse these effects. Conclusion SIRT1 overexpression inhibits tunicamycin-induced ERS and cell apoptosis, and further attenuates p38/NF-κB activation in chondrocytes.