Current therapies for rheumatoid arthritis, including anti-inflammatory agents and immunomodulators, primarily target common inflammatory mechanisms. However, the efficacy of most bioactive compounds claimed to possess anti-arthritic properties remains mechanistically unproven, particularly against progressive conditions like pannus development. This study investigates the pharmacokinetics, toxicity, and impact of reported anti-arthritic polyphenols on HIF-regulated pannus development in rheumatoid arthritis through in silico and in vitro approaches. Eighty bioactive compounds with documented anti-arthritic properties were selected from the literature and subjected to sequential evaluation of pharmacodynamic and pharmacokinetic activity. The study identified five promising candidates qualified to perform in vivo toxicity and in vitro biochemical assays. Toxicity testing using Galleria mellonella larvae indicated dose-dependent effects on the midgut, with no mortality observed at doses up to 2000 mg/kg body weight. In vitro assays, including antioxidant and anti-inflammatory evaluations, further validated the therapeutic potential of these compounds. Compounds that satisfied all predictive criteria were subjected to molecular interaction analysis against hub-gene targets implicated in HIF-regulated angiogenesis in rheumatoid arthritis. RA-associated proteins were identified from NCBI-GEO and DisGeNET (GWAS) databases. Functional annotation and protein-protein interaction analysis identified IL-6, IL-1β, HIF-1α, PPARG, and TIMP1 as key hub targets. Molecular docking using PyRx revealed the binding affinities of the selected bioactive compounds against these targets. These findings suggest that the screened bioactive polyphenols exhibit low toxicity and hold potential as regulators of HIF-mediated angiogenesis in rheumatoid arthritis, offering a novel therapeutic approach for progressive disease management. © 2025 Elsevier B.V., All rights reserved.