Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that primarily effect synovial joints, leading to primarily cartilage and bone damage. The present study aimed to develop Escin loaded biodegradable nanoparticles (ESNPs) through the ionic gelation method using chitosan as biodegradable polymer, followed by comprehensive characterization of the nanoparticles. Additionally, the in-vivo anti-arthritic efficacy of the nanoparticles was assessed by Complete Freund's Adjuvant (CFA). ESNPs has 213 nm size, + 0.4 mV charge, and a polydispersity index of 0.42 with loading capacity of 81%, and entrapment efficiency of 87%. XRD revealed a semi-crystalline structure of ESNPs, whereas scanning electron microscopy suggested a spherical, uneven shape. For anti-arthritic potential, 0.15 ml CFA was injected in left hind paw in all rats aside from normal rats at day 1. From the eighth to twenty-eighth day, ESNPs (2.5, 5, and 10 mg/kg) and Escin (ES 10) were given orally, whereas blank nanoparticles were given to normal and disease controls. The standard reference medication utilized was methotrexate (1 mg/kg). In treated rats, paw edema was notably reduced and body weight was restored by ESNPs at 10 mg/kg. At all dosage levels, ESNPs demonstrated strong analgesic effects in arthritic rats. When compared to ES 10 and disease control, ESNPs significantly adjusted the impaired blood parameters, oxidative stress markers, and neurotransmitters levels as evident from the histological analysis of the treated rats' ankle joint. Treatment with ESNPs at 10 mg/kg, significantly altered the expression of IL-4, IL-6, cyclooxygenase-2, nuclear factor kappa-β and TNF-α. The results indicated that, in comparison to ES 10 and methotrexate, ESNPs, primarily at 10 mg/kg, demonstrated strong anti-arthritic activity.