Our study aimed to determine the effects of sodium tanshinone IIA sulfonate (STS) on proliferation, migration, invasion, and inflammation in rheumatoid arthritis human fibroblast-like synoviocytes (RA-HFLSs). Firstly, results demonstrated STS reduced proliferation, migration, invasion in HFLSs. Also, we found that STS could alleviate the reorganizations of F-actin cytoskeleton in TNF-alpha-treated HFLSs. In addition, STS decreased the production of IL-1 beta, IL-6, MMP-1, and MMP-3 in TNF-alpha-treated RA-HFLSs. Further study showed that STS blocked MAPK/NF-kappa B activations in TNF-alpha-stimulated RA-HFLSs. Moreover, we illustrated that STS could alleviate rheumatoid arthritis progression and prevent inflammation damage in joint tissues of collagen-induced arthritis (CIA) mice. Taken together, this study suggested that STS inhibited proliferation, migration, invasion, and inflammation of RA-HFLSs by blocking MAPK/NF-kappa B pathways.