2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-2,3-dihydrochromen-4-one (eriodictyol), a flavonoid compound, was proved to possess anti-inflammatory, antioxidative, and antiarthritis activities. However, the effects of eriodictyol on the rheumatoid proliferation, apoptosis, and inflammatory response of arthritis fibroblast-like synoviocytes (RA-FLS) remain unclear. Thus, the objective of this study was to examine the effects of eriodictyol on RA-FLS survival, apoptosis, and inflammatory response, and further explore the potential underlying mechanisms. Our results showed that eriodictyol inhibited the survival of RA-FLSs and promoted its apoptosis. Eriodictyol significantly reduced RA-FLS secretion of tumor necrosis factor α, interleukin 6 (IL-6), IL-8, and IL-1β. Furthermore, eriodictyol prevented the activation of the protein kinase B (AKT) pathway and increased the expression of forkhead box O1 (FOXO1) in RA-FLS. FOXO1 silence reversed the effects of eriodictyol on RA-FLS survival, apoptosis, and inflammation. In conclusion, these findings indicated that eriodictyol inhibits the cell survival and inflammatory response in RA-FLS, and the AKT/FOXO1 signaling pathway is involved in the effect of eriodictyol on the RA-FLS. Thus, eriodictyol might be a potential therapeutic agent for the treatment of rheumatoid arthritis. © 2019 Wiley Periodicals, Inc.