Sesuvium sesuvioides(Fenzl) Verdc (Aizoaceae) has been traditionally used in the treatment of inflammation, arthritis, and gout. However, its antiarthritic potential has not been evaluated scientifically. The current study was designed to assess the antiarthritic properties of then-butanol fraction ofS. sesuvioides(SsBu) by phytochemical analysis,in vitroandin vivopharmacological activities, andin silicostudies. Phytochemical analysis showed total phenolic contents (90.7 ± 3.02 mg GAE/g) and total flavonoid contents (23.7 ± 0.69 mg RE/g), and further analysis by GC-MS identified possible bioactive phytocompounds belonging to phenols, flavonoids, steroids, and fatty acids. Thein vitroantioxidant potential of SsBu was assessed by DPPH (175.5 ± 7.35 mg TE/g), ABTS (391.6 ± 17.1 mg TE/g), FRAP (418.2 ± 10.8 mg TE/g), CUPRAC (884.8 ± 7.97 mg TE/g), phosphomolybdenum (5.7 ± 0.33 mmol TE/g), and metal chelating activity (9.04 ± 0.58 mg EDTAE/g). Moreover, in thein vitrostudies, inhibition (%) of egg albumin and bovine serum albumin denaturation assays showed that the anti-inflammatory effect of SsBu at the dose of 800 μg/ml was comparable to that of diclofenac sodium used as a standard drug. Thein vivoantiarthritic activity was assessed to determine the curative impact of SsBu against formalin-induced (dose-dependent significant (p< 0.05) effect 72.2% inhibition at 750 mg/kg compared to standard; 69.1% inhibition) and complete Freund’s adjuvant-induced arthritis (40.8%; inhibition compared to standard, 42.3%). SsBu significantly controlled PGE-2 level compared to the control group (p< 0.001) and restored the hematological parameters in rheumatoid arthritis. Treatment with SsBu significantly reduced oxidative stress by reinstating superoxide dismutase, GSH, and malondialdehyde along with pro-inflammatory markers (IL-6 and TNF-α) in arthritic rats. Molecular docking revealed the antiarthritic role of major identified compounds. Kaempferol-3-rutinoside was found to be more potent for COX-1 (−9.2 kcal/mol) and COX-2 inhibition (−9.9 kcal/mol) than diclofenac sodium (COX-1, −8.0 and COX-2, −6.5 kcal/mol). Out of the 12 docked compounds, two for COX-1 and seven for COX-2 inhibition showed more potent binding than the standard drug. The results from thein vitro,in vivo, andin silicoapproaches finally concluded that then-butanol fraction ofS. sesuvioideshad antioxidant and antiarthritic potential, which may be due to the presence of potential bioactive compounds.