Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder that has long been hampered by limited treatment efficacy and significant side effects. Tumor necrosis factor-α (TNF-α) plays a pivotal role in RA pathogenesis by binding to its receptor (TNFR) and activating the downstream nuclear factor-kappa B (NF-κB) signaling pathway, which promotes the transcription of pro-inflammatory genes and perpetuates disease progression. Blocking the TNF-α–TNFR interaction thus represents a promising therapeutic strategy for RA. In this study, we identified a natural compound, 1-norbetulonic acid (DOCA), that disrupts the binding between TNF-α and TNFR, leading to therapeutic benefits in RA. Our results show that DOCA inhibits TNF-α-induced activation of the NF-κB pathway in human fibroblast-like synoviocytes and MH7A cells, and prevents nuclear translocation of the p65 subunit. Notably, DOCA demonstrated significant therapeutic efficacy in a mouse model of RA. Together, these findings support the hypothesis that DOCA alleviates RA by blocking TNF-α–TNFR signaling, underscoring its potential as a natural product-derived inhibitor of this interaction and highlighting a viable approach for the discovery of TNF-α/TNFR-targeted natural therapeutics.