Acmella paniculata has been traditionally used in folklore medicine to alleviate pain and manage articular rheumatism. This study explores its potential anti-inflammatory and antiarthritic effects through in silico and in vivo approaches. A. paniculata bioactives' antiarthritic mechanisms were elucidated using computational techniques, namely, gene set enrichment analysis, network pharmacology, molecular docking, and molecular dynamics (MD) simulations using KEGG pathway analysis, PyRx, Discovery Studio, and GROMACS tools. A. paniculata hydroalcoholic extract (APE) and the ethyl acetate fraction (APF) were analyzed via LC‒MS for phytochemical profiling. In vivo studies assessed anti-inflammatory and antiarthritic potential in carrageenan-induced paw edema and complete Freund's adjuvant (CFA)-induced arthritis models in Wistar rats. Ferulic acid, isoferulic acid, and acetyl aleuritolic acid were identified as bioactives that targeted RELA, a key NF-κB component. Stable interactions were confirmed through docking and MD simulations. LC‒MS verified these compounds in APE and APF. In vivo study revealed significant reductions in paw volume, arthritis scores, and inflammatory markers (CRP, RF, IL-6, and TNF-α) and improved histopathological outcomes in the APE and APF-treated groups compared to the CFA. These findings highlight the anti-inflammatory and antiarthritic potential of A. paniculata via multi-protein modulation, particularly NF-κB signaling, and it can be utilized as a promising therapeutic for rheumatoid arthritis.