**Background:** Wounds represent a significant global healthcare burden, with approximately 6.7 million people worldwide suffering from chronic wounds as of 2020. The global chronic wound care market is projected to grow from USD 12.36 billion in 2022 to USD 19.52 billion by 2029 at a CAGR of 6.7%. Additionally, an estimated 100 million patients per year in the developed world are affected by scars from 55 million elective surgeries and 25 million trauma-related surgeries. Wound healing is a complex four-phase process—hemostasis, inflammation (0–3 days), proliferation (3–24 days), and remodeling (24–365 days)—that requires coordinated cellular and molecular interactions. Current treatments including wound dressings, antibiotics, and surgical debridement have significant limitations: antibiotic resistance rates in wound infections approach 70%, and more than 500,000 deaths annually are attributed to antibiotic-resistant infections, with projections of 10 million deaths per year by 2050. Vasoconstrictors such as nicotine and cocaine impair wound healing by causing tissue hypoxia, while ergotamine derivatives have been recommended for prohibition by the European Medicines Agency due to unfavorable risk-benefit profiles. Flavonoids, phenolic compounds abundant in fruits, vegetables, tea, and medicinal plants, have emerged as promising natural alternatives due to their anti-inflammatory, antioxidant, antibacterial, and pro-angiogenic properties.
**Methods:** This narrative review compiled existing evidence from in vitro scratch assays, in vivo animal models (primarily rodent wound excision models), and clinical trials investigating flavonoid-mediated wound healing. The authors systematically examined the role of flavonoids across multiple signaling pathways including Wnt/β-catenin, Hippo, TGF-β, Hedgehog, JNK, Nrf2/ARE, NF-κB, MAPK/ERK, Ras/Raf/MEK/ERK, PI3K/Akt, and NO pathways. Eight clinical trials were reviewed, encompassing studies on quercetin, hesperidin, micronized purified flavonoid fraction (MPFF), anthocyanins, propolis, and flavonoid-rich plant extracts from Achillea millefolium and Mimosa tenuiflora.
**Key Results:** In vitro studies demonstrated that quercetin-3-oleate at 1 μM increased wound-healing rate by 51% with slight TGF-β production and MMP-9 release. Quercetin-loaded liposomal hydrogel produced 52.26% more wound contraction in rats within four days compared to controls. In diabetic rat models, kaempferol achieved 92.12% wound healing in excisional wounds after 14 days of treatment. Hesperidin accelerated wound closure in diabetic foot ulcers (less than 21 days) by elevating VEGF-c, Ang-1/Tie-2, TGF-β, and Smad-2/3 mRNA expression. A hydrogel containing flavonoid glycoside (H2 formulation at 0.0025% w/w) promoted wound closure beginning on day 4 in mouse models. In bone defect studies, 100 mg/kg/day of flavonoid was identified as the optimal dosage for promoting osteoblast differentiation and angiogenesis. In clinical trials, a nano-hydrogel containing quercetin and oleic acid applied to diabetic foot skin wounds for eight months outperformed hyaluronic acid in 56 diabetes mellitus patients (28 men, 28 women). MPFF combined with compression therapy in 723 patients with venous leg ulcers surpassed conventional therapy by 32% in healing rate after six months. Plant-derived quercetin cream achieved wound closure in 2–4 days in 35% of 40 male volunteers with oral wounds. Anthocyanin gel from Zea mays and Clitoria ternatea extracts accelerated oral wound repair in 68 orthodontic patients (ages 18–25) within 7 days. Propolis (15% water solution) dramatically accelerated wound healing after 14 days in 33 patients (ages 18–45) following sacrococcygeal pilonidal sinus surgery. Mimosa tenuiflora reduced chronic venous leg ulcer size by 93% at week 8 in a study with fewer than 50 patients. Flavonoid-loaded silver nanoparticles from Madhuca longifolia enhanced wound healing by up to 80.33%.
**Clinical Implications:** Flavonoids represent a promising, low-cost alternative for wound management with minimal side effects compared to conventional treatments. Their multi-targeted mechanism of action—simultaneously modulating inflammation, oxidative stress, angiogenesis, and collagen synthesis—addresses the complex pathophysiology of chronic wounds. The antibacterial properties of flavonoids against wound pathogens including Staphylococcus aureus and Pseudomonas aeruginosa offer additional therapeutic value, particularly given the rising threat of antibiotic resistance. However, the authors note significant limitations: most studies have not progressed to Phase 3 clinical trials, clinical findings are inconsistent, and the majority of advancements remain in preclinical stages. Future directions include integrating flavonoids with nanotechnology-based drug delivery systems (e.g., chitosan hydrogels, carbonized nanogels with copper sulfide nanoclusters) to enhance bioavailability and therapeutic efficacy. The review emphasizes the need for standardized flavonoid formulations, rigorous clinical validation, and investigation of dose-dependent effects and synergistic interactions with other bioactive compounds.