Background: Homeopathy is a popular form of complementary and alternative medicine. Guaiacum extract is said to be useful for pain and inflammation, but there appears to be no scientific evidence to support this.Aims: The aim of the present study was to evaluate the anti-rheumatic and anti-oxidant activity of homeopathic preparations of Guaiacum officinale (Gua) on experimental animal model.Design: Rheumatoid arthritis (RA) was induced in male albino rats by Freund’s complete adjuvant (FCA) at a dose of (0.25 mg heat killed Mycobacterium tuberculosis/ml of emulsion). Gua mother tincture (MT) (prepared from the latex part of the plant) (MT), Gua 30cc and 200cc were purchased commercially from King Company, Kolkata, India. Male albino Wistar rats (130 ± 10 g) were divided into 6 groups: Sham control; Arthritis control; Standard treatment indomethacin (0.25 mg 100 g−1 p.o. × 5 alternative days), Gua MT (1 ml kg−1 p.o. × 5 days) treated; Gua (30c 1 ml kg−1 p.o. × 5 days) treated; Gua (200c; 1 ml kg−1 p.o. × 5 days) treated. Anti-rheumatic activity was examined through physical, urinary, serum parameters. All the results were expressed in terms of mean ± SEM (statistical error of mean n = 6) at each dose level. The level of significance was determined through one-way analysis of variance (ANOVA), p < 0.05 was considered significant.Results: It was observed that body weight, ankle and knee diameter, urinary parameters (hydroxyproline (OH-P), glucosamine, calcium (Ca2+), creatinine (CRE), phosphate (PO43−)), serum ACP (acid phosphatase)/ALP (alkaline phosphatase)/Ca2+/CRE/PO43−/gamma-glutamyl transferase (GGT)/Lipid peroxidation (LPO)/Glutathione (GSH)/Superoxide dismutase (SOD)/Catalase, serum GGT, serum interleukins like IL-1β/CINC-1/PGE2/TNF-α/IL-6, IL-12/IL-4/IL-6 levels were significantly affected. After treatment with Guaiacum in all 3 regimes was associated with normalization of these parameters compared to control group.Conclusion: These findings suggest that homeopathic G. officinale possesses anti-rheumatic and anti-oxidant activity in experimental animal and these activities may be more significant in higher potencies.