Bone marrow mesenchymal stem cells (BMSCs) are widely used for therapeutic applications in tissue engineering and regenerative medicine. Nevertheless, the function of BMSCs is adversely affected by senescence. Thus, understanding the molecular mechanisms that contribute to BMSC senescence is critical for the development of BMSC-based tissue engineering and regenerative medicine. In this study, senescent BMSCs were characterized with >80 % of BMSCs stained positive for SA-β-gal, increased expressions of senescence-related genes (p16INK4a and p21Waf1). These senescent characters were accompanied by elevated autophagic activity, up-regulation of interleukin 6 (IL-6), IL-8, and FoxO3a. Autophagic activity inhibition alleviated the senescent state with reduced levels of IL-6 and IL-8 during BMSC senescence. The enhanced autophagic activity upregulated the levels of IL-6 and IL-8 which is associated with up-regulation of FoxO3a, and knockdown of FoxO3a reduced IL-6 and IL-8 expression in senescent BMSCs. Therefore, this study indicated the pivotal role of autophagic activity in the expressions of IL-6 and IL-8 during BMSC senescence, which is regulated by FoxO3a.Copyright © 2022. Published by Elsevier Inc.