In recent decades, the use of herbs and plants has been of great interest, as they have been the sources of natural products, commonly named as bioactive compounds. In specific, the natural compounds from the Capparaceae family which has been proved to have antioxidant, anti-inflammatory, antimicrobial and anti-carcinogenic activities, by several studies. Cleome arabica L. (CA) specie is the most used medicinal plants in Tunisia and elsewhere in North African countries for treatment of various diseases including diabetes, rheumatism, inflammation, cancer, and digestive disorders. The current work was undertaken to estimate the total phenolic, flavonoid and condensed tannin contents, to identify and quantify the polyphenolic compounds, and to evaluate the antioxidant and the anti-inflammatory proprieties of CA fruits extract against formalin induced chronic inflammation in Female Wistar rats. In fact, the antioxidant activity was tested by Diphenyl-1-Picrylhydrazyl free radical scavenging (DPPH), Ferric reducing antioxidant power (FRAP) and Nitric Oxide radical (NO·). Anti-inflammatory effect of fruits extract was examined using formalin (2%) induced paw edema in rats. Molecular docking tools were used to investigate the interaction of some compounds from CA fruits extract with the cyclooxygenase-2 (COX-2) target protein. Our results showed that, the total phenolic, flavonoid and tannins contents, which were assessed by the Folin-Ciocalteu, Quercetin, and Catechin methods, respectively, were 230.22 mg gallic acid equivalent/g dry weight (mg GAE/g DW), 55.08 mg quercetin equivalent/g dry weight (QE/g DW) and 15.17 mg catechin equivalents/g dry weight (CatE/g DW), respectively. HPLC analysis revealed the presence of five polyphenolic compounds whose catechin was found to be the most abundant compounds. The antioxidant activity of extract was quantified by DPPH, FRAP and NO· tests and IC50 reached the values of 3.346 mg/mL, 2.306 and 0.023 mg/mL, respectively. Cleome fruits ameliorated the histological integrity of the skin and alleviated the disruptions in hematological parameters (WBC, LYM, RBC, and HGB), inflammatory cytokines (IL-1β, IL-6, TNF-α), C-reactive protein, and some oxidative stress markers (TBARS (−49%) and AOPP (−42%) levels, SOD (+33%) and GPx (+75%) activities, and GSH (+49%) content) induced by formalin injection. Moreover, the in-silico investigation had shown that CA fruits extract compounds have a stronger interaction with COX-2 active site, more than the reference drug “indomethacin” (two H-bonds). Our research gives pharmacological backing to the healthcare utilization of Cleome plant in the treatment of inflammatory diseases and oxidative harm.