Telomeres, the repetitive DNA-protein complexes capping eukaryotic chromosomes, preserve genomic stability and regulate cellular replicative capacity. Progressive telomere shortening, coupled with diminished telomerase activity, is a hallmark of aging and contributes to cellular senescence, tissue degeneration, and the onset of age-related diseases. Conversely, telomerase overactivation in malignant cells enables uncontrolled proliferation, positioning telomere biology as a dual therapeutic target in longevity and oncology. Plant-derived compounds possess diverse structural classes such as polyphenols, flavonoids, triterpenoid saponins, polysaccharides, lignans, alkaloids, carotenoids, amino acids, and fatty acids that can modulate telomere length and telomerase activity via multiple molecular pathways. These include antioxidant and anti-inflammatory actions, regulation of key genes such as hTERT, SIRT1, and c-Myc, modulation of PI3K/Akt, JAK/STAT, and ERK signaling, and stabilization or destabilization of G-quadruplex DNA structures. Compounds such as resveratrol, epigallocatechin gallate, astragaloside IV, cycloastragenol, and ginsenoside Rg1 have demonstrated telomerase activation or inhibition in a context-dependent manner, influenced by concentration, cell type, and disease state. This review categorizes plant-derived positive and negative telomere/telomerase modulators, detailing their sources, mechanisms of action, experimental evidence, and the formulation challenges that hinder clinical translation, such as low bioavailability, instability, and variability in phytochemical content. By integrating molecular insights with pharmacological perspectives, this review highlights the potential of plant-derived agents as multi-target interventions in aging and cancer. Advancing this field will require rigorous pharmacokinetic profiling, standardized preparations, and longitudinal clinical studies to bridge the gap between laboratory findings and real-world therapeutic outcomes.
