<p>Nanomedicines anticipate drug delivery to inflamed tissues in rheumatoid arthritis (RA) with greater efficacy and lesser side effects. This study investigates the anti-arthritic potentials of Hesperidin (HP) loaded in gum acacia (GA) stabilized green silver nanoparticles (AgNPs). Synthesized GA-AgNPs were characterized through UV–vis spectrophotometer, zetasizer and atomic force microscope (AFM). The HP and its loaded NPs were tested for RA in Complete Freund’s adjuvant (CFA) induced arthritis model. GA-AgNPs were found in nano-range size with negative charge, spherical shape and loaded increased HP amount. HP loaded GA-AgNPs showed minimal arthritic score exhibiting mild to moderate tissue swelling, reduced degenerative changes along with mild articular changes. Histopathological analysis revealed comparatively lesser influx of inflammatory cells and diminished granulamatous inflammation in ankle joints tissues in the presence of HP loaded GA-AgNPs. RT-PCR revealed that HP loaded GA-AgNPs significantly reduced the TLRs mRNA expression. Results validate GA stabilized green AgNPs as stable nano-cargos for targeted delivery of HP for restoring the progression of RA.</p