Background <p>Chronic inflammatory diseases are major global health challenges driven by persistent oxidative stress and dysregulated immune signalling. Plant-derived indole alkaloids are structurally diverse metabolites found in medicinal plants, fungi and marine organisms; that exhibit potent multi-target anti-inflammatory and antioxidant activities.</p> Aim <p>This review integrates current evidence on the chemistry, sources and mechanistic pathways of plant-derived indole alkaloids, emphasizing their modulation of key inflammatory axes, including NF-κB, JAK/STAT, MAPK, PI3K/AKT, NLRP3 inflammasome and AhR signalling.</p> Methods <p>A thorough search of PubMed, Scopus and Google Scholar databases was conducted up to December 2025. Eligible studies included preclinical, clinical and review articles addressing the effects of indole alkaloids on inflammatory mediators, oxidative stress markers and disease endpoints.</p> Results <p>Indole alkaloids have been proven to suppress pro-inflammatory mediators; like TNF-α, IL-1β, IL-6, NO, PGE₂, COX-2 and iNOS; while enhancing antioxidant defences and cytoprotective responses. Representative scaffolds have demonstrated promising protective effects in colitis, osteoarthritis, COPD, atherosclerosis, chronic kidney disease and inflammation-driven cancers through restoration of epithelial and endothelial barriers, immune-cell reprogramming and rebalancing of organ-specific crosstalk. Monoterpenoid and tryptophan-derived indole alkaloids particularly integrated AhR and NF-κB/STAT3 pathways, supporting microbiota- and organ-selective therapeutic prospects.</p> Conclusions <p>Plant-derived indole alkaloids emerge as promising yet underexploited multi-target scaffolds for chronic inflammatory diseases, primarily supported by preclinical evidence. Future advances in synthetic biology, metabolomics and rational hybrid design are essential to overcome translational barriers and enable clinically scalable development of this chemotype.</p>