Lingzhi or reishi mushroom, <i>Ganoderma lucidum</i>, is a medicinal mushroom quite widely developed as herbal medicine because it has acted as an anticancer, antitumor, antioxidant, and anti-inflammatory. The active mycochemical compounds of <i>G. lucidum</i> mushrooms, such as flavonoids and polysaccharides, can suppress the release of pro-inflammatory cytokines and prevent lipid peroxidation due to oxidative stress. Rheumatoid arthritis (RA) is an autoimmune disease where the exact cause is unknown, and RA prevalence continues to increase yearly. In patients with RA, joint damage and inflammation occur. This study aims to evaluate the effectiveness of <i>G. lucidum </i>nanogels as anti-arthritis, anti-inflammatory, and antioxidative. The research method was a true experiment using a control group and treatment group that randomly assigned, using 24 male Wistar rats (<i>Rattus norvegicus</i>) induced with complete Freund's adjuvant (CFA) 0.1 mL. The rats were divided into six groups; healthy control/HCt (did not receive the treatment), negative control/NCt (induced by CFA), and positive control/PCt (given 0.012 diclofenac sodium). TG1 (given 250 mg <i>G. lucidum</i> nanogels), TG2 (given 500 mg <i>G. lucidum</i> nanogels), TG3 (given 750 mg <i>G. lucidum</i> nanogels). IgG, eNOS, IL-1β, COX-2, NOS, TNF-α, and IL-6 parameters were measured using ELISA, and the data obtained were analyzed by one-way ANOVA using SPSS (<i>P</i> < 0.05). The results showed that administering <i>G. lucidum</i> nanogels significantly reduced IgG, NOS, TNF-α, COX-2, IL-1β, and IL-6 and increased eNOS levels. The anti-inflammatory and antioxidative activities in suppressing pro-inflammatory cytokines and increasing eNOS levels prove that the nanogel extract <i>G. lucidum</i> have the potential to be developed as anti-arthritis natural therapeutic.