Chronic inflammation underlies numerous pathological conditions including cardiovascular diseases, metabolic disorders, neurodegenerative diseases, and cancer, representing a significant burden on global healthcare systems. Traditional anti-inflammatory therapeutics often present limitations including adverse effects, patient non-responsiveness, and drug resistance, necessitating innovative approaches to identify novel anti-inflammatory agents. Plant-based bioactive compounds have emerged as promising candidates due to their diverse chemical structures, multi-target mechanisms, and historical validation in traditional medicine systems. This article examines the contemporary landscape of plant-derived anti-inflammatory agent discovery, emphasizing molecular mechanisms, high-throughput screening methodologies, target identification and validation strategies, and lead optimization processes. We discuss critical bioactive phytochemical classes including polyphenols, alkaloids, terpenoids, and organosulfur compounds, elucidating their interactions with key inflammatory mediators such as nuclear factor kappa B, cyclooxygenase enzymes, lipoxygenases, and inflammasome components. Advanced preclinical strategies incorporating systems biology, pharmacokinetic optimization, and translational disease models are presented alongside clinical development innovations that bridge laboratory discoveries with therapeutic applications. Computational and artificial intelligence-driven approaches enhancing compound screening, structure-activity relationship prediction, and drug repurposing are comprehensively reviewed. Challenges including bioavailability limitations, standardization complexities, regulatory hurdles, and ethical considerations in phytopharmaceutical development are critically examined. This comprehensive review provides insights into the translational pathway from phytochemical identification to evidence-based anti-inflammatory therapeutics, offering perspectives on future directions in plant-based precision medicine for inflammation management.