Cancer is the focus of much research, primarily due to its high prevalence and the unsatisfactory standard treatments currently in use. A major problem is the non-specific nature of these treatments, which reduces their efficacy and leads to undesirable side effects. G-quadruplexes (G4), secondary structures of DNA formed spontaneously at sites with a high concentration of guanine, are frequently discussed as potential targets for specific therapy. In this study, the effect of selected natural compounds (gallic acid, EGCG, epicatechin, ellagic acid, and brucine) on G4 was investigated. Using a ThT competitive assay, CD spectroscopy, nuclear magnetic resonance and molecular dynamics simulations, the binding ability of all selected natural compounds to G4 structures was confirmed. The primary forces involved in this binding are weak π-interactions between the aromatic rings of G4 guanines and the natural compounds. However, this binding is weak, and the presence of these compounds does not affect the stability or formation of G4. In the second part of the study, the effect of these compounds was examined using cellular models. First, a yeast isogenic system was used to investigate the effect of G4 presence near the p53 response element on p53 protein activity, and subsequently, the effect of natural compounds on this activity was examined. The measurements show that the substances we selected affect the basal activity of the p53 protein; however, if G4 is present downstream of the response element, there is an increase in p53 protein activity compared to activity in the absence of G4. In the final section, the effect on the viability of mammalian cell lines (HDF, HaCaT, U87, and MCF-7) was assessed. Within the concentration range we used, where the highest concentration was 125 µM, an IC50 value was achieved only for the HDF cell line with gallic acid. All selected compounds are therefore suitable and sufficiently safe for use in subsequent experiments and for disease prevention. The final experiment, which involved immunological staining of skin cells, verified the ability of these compounds to penetrate the nucleus and bind to G4 even under physiological conditions. The most effective binders were epicatechin, EGCG, and brucine.