Arthritis is a painful inflammatory illness, characterized by joint destruction and disability. Non-steroidal anti-inflammatory drugs (NSAIDs) are applied extensively as pain relievers, however, their prolonged administration can result in undesirable side impacts on various body organs. Ashwagandha (Withania somnifera) has drawn researchers' consideration of its several medical uses. The current study investigated the anti-inflammatory action of ashwagandha (Ash) versus that of diclofenac sodium (Dic) via the evaluation of paw thickness, hematological, biochemical, inflammatory parameters, and histopathological alteration in rats. Rats were distributed into 6 groups and kept for 21 days: the control group; received normal saline orally, the Ash group; was orally treated with Ash (200 mg/kg body weight), the Dic group; was orally treated with Dic (2 mg/kg b.wt), Arthritic group (Arth); rats were subjected to 0.1 ml sub-plantar inoculation of formalin (2.5%) at right hind paw on day 1 and received normal saline orally, Arth+Ash group; arthritis was induced as explained in Arth group then treated with Ash (at the same dose as Ash group) orally, Arth+Dic group; arthritis was induced as explained in Arth group then treated with Dic (at the same dose as Dic group) orally. Paw thickness was significantly increased in Arth rats than the control ones at various estimated times along the experiment, however, a significant decline was recorded in Arth+Ash and Arth+Dic groups. Upon completion of the research (21 days), blood and tissue specimens were harvested. Hematological outcomes announced normocytic normochromic anemia in Arth rats, and this effect was alleviated upon the administration of Ash to Arth rats. While Dic had negative drawbacks on erythrogram. Serum ALT, urea, creatinine, IL-6, CRP, COX2, and hepatic TOC exhibited substantial increment along with substantial decrement in serum IL-10 and hepatic TAC in the Arth group. Meanwhile, the Arth+Ash and Arth+Dic groups showed significant improvement in these parameters in comparison to the Arth group. In addition, our histopathological assessment illustrated the adverse sequel of Dic on miscellaneous rat body tissues and that Ash displayed invulnerable action. Lastly, oral administration of W. sominefra extract to rats with arthritis induced by formalin, remarkably decreased paw thickness and alleviated unfavorable modifications in all measured variables in a way better than diclofenac. Then, W. sominefra can be used to treat rheumatoid arthritis without causing any harm because it has anti-arthritic and anti-inflammatory impacts.