<p>Inflammation is an immediate physiological response for defense and tissue repair against external stress, however it contributes to the pathogenesis of several chronic diseases when dysregulated. Plant-derived natural products, including flavonoids, terpenoids, alkaloids, phenolic acids, tannins, and essential oils, possess potential anti-inflammatory activity through modulation of key signaling pathways including NF-κB, MAPKs, PI3K/Akt, and inflammasomes. These compounds influence immune responses by promoting the polarization of anti-inflammatory macrophages, regulating T-cell responses and inhibiting neutrophil activation. Additionally, these compounds possess significant antioxidant properties that alleviate oxidative stress and downstream inflammatory signaling. Despite robust preclinical and evolving clinical evidence, their therapeutic potential is limited by several pharmacokinetic challenges, including poor solubility, rapid metabolism, and slight bioavailability. Here, the use of advanced drug delivery approaches, including nanoparticles, liposomes, and phytosomes, together with bioenhancers and prodrugs can be crucial in improving systemic exposure and efficacy of these compounds. Integrating omics technologies and artificial intelligence can accelerate the identification and optimization of novel anti-inflammatory phytochemicals. Nevertheless, several challenges persist, including standardization, quality control, regulatory approval, and safety assessments. This review summarizes the pharmacological mechanisms, pharmacokinetic limitations, clinical evidence, and provide future directions for plant-derived anti-inflammatory agents. It highlights their potential use as safe, effective, and affordable therapeutic options against inflammation-related diseases.</p><p></p>