BACKGROUND: Luteolin and fisetin are emerging lead flavonoids with significant therapeutic promise due to their wide-spectrum modulation of key molecular signalling pathways implicated in oxidative stress, inflammation, metabolic dysfunction, neurodegeneration, and cancer. However, mechanistic integration, SAR-based interpretation, and translational pharmacokinetic understanding remain fragmented. This systematic review aims to consolidate molecular targets, signalling network interactions, structure-activity relationships, pharmacokinetic limitations, and clinical advancement potential of luteolin and fisetin to define their future drug development relevance. METHODS: A systematic PRISMA-based strategy was employed across PubMed, Scopus, Web of Science, and Google Scholar up to March 2025. Eligible in vitro, in vivo, and clinical studies evaluating the mechanistic activity, SAR influence, pharmacokinetics, or therapeutic efficacy of luteolin/ fisetin were included. Data were narratively synthesised due to heterogeneity in study designs. RESULTS: A total of 127 studies met eligibility criteria. Both flavonoids demonstrated multi-target and multi-pathway modulation involving NF-κB, Nrf2, MAPK, PI3K/Akt, apoptotic regulators, neuroinflammatory signals, and metabolic pathway nodes. SAR analysis identified hydroxylation patterns, O-methylation, and glycosylation as determinants of potency, membrane permeability, and ADME properties. Pharmacokinetic evidence revealed poor solubility, low oral bioavailability, and rapid metabolism, though nanoformulations, prodrugs, and targeted delivery systems significantly enhanced systemic exposure and therapeutic index. CONCLUSION: Luteolin and fisetin represent valuable flavonoid scaffolds with highly relevant druggable molecular targets. Despite promising mechanistic depth, clinical validation remains limited, and pharmacokinetic barriers warrant strategic optimisation. Future translational advancement should prioritise structure-guided analogue development, BBB penetration enhancement, and biomarker-linked clinical endpoints.