Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovial inflammation, cartilage degradation, and progressive joint dysfunction. Conventional therapies, while effective in slowing disease progression, are limited by adverse effects, incomplete remission, and high costs. Natural products, such as Curcuma longa (turmeric), offer a promising alternative due to their anti-inflammatory, antioxidant, and multi-target pharmacological properties. In this study, a network pharmacology and computational approach was employed to investigate the multi-target therapeutic potential of Curcuma longa against RA. A curated library of non-toxic, drug-like phytochemicals with reported anti-RA activity was developed through data mining and filtered using ADMET screening, yielding 111 compounds. Differentially expressed genes (DEGs) associated with RA were identified via meta-analysis of synovial tissue microarray datasets GSE55457 and GSE55235, resulting in 1,473 DEGs. Gene set enrichment analysis (GSEA) revealed key RA-associated pathways, and a protein–protein interaction (PPI) network analysis identified 31 hub genes. Compound–target mapping highlighted significant interactions between Curcuma longa phytochemicals and RA-associated hub genes, with MMP13 emerging as a central therapeutic target due to its critical role in extracellular matrix degradation, cartilage erosion, and joint destruction. Molecular docking studies demonstrated strong binding affinities (< –8 kcal/mol) of lead compounds, including cyclocurcumin, curcumin, and (1E,4E)-1-(4-hydroxy-3-methoxyphenyl)-5-(4-hydroxyphenyl)-1,4-pentadiene-3-one, to MMP13, mediated via hydrogen bonding and hydrophobic interactions. Molecular dynamics (MD) simulations over 200 nanoseconds confirmed the stability of these ligand–protein complexes, supporting their potential inhibitory effects on matrix degradation pathways. Overall, this study provides mechanistic insights into the multi-target, multi-pathway modulation of RA by Curcuma longa phytochemicals. Cyclocurcumin and curcumin derivatives are highlighted as promising candidates for further in vitro and in vivo validation, paving the way for their development as adjunct or alternative therapeutic agents in RA management.