Biological systems are frequently exposed to excessive reactive oxygen species, causing a disturbance in the cells natural antioxidant defence systems and resulting in damage to all biomolecules, including nucleic acids. In fact, oxidative DNA damage is described as the type of damage most likely to occur in neuronal cells. In this study, three polyphenolic compounds, luteolin, quercetin and rosmarinic acid, were investigated for their protective effects against oxidative DNA damage induced in PC12 cells, a neuronal cell model. Although luteolin and quercetin prevented the formation of strand breaks to a greater extent than rosmarinic acid, this last one presented the highest capacity to repair strand breaks formation. In addition, rosmarinic acid was the only compound tested that increased the repair of oxidized nucleotidic bases induced with the photosensitizer compound [R]-1-[(10-chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizin-1-yl) carbonyl]-2-pyrrolidine-methanol (Ro 19–8022). The activity of repair enzymes was indicated by the in vitro base excision repair assay, using a cell-free extract obtained from cells previously treated with the compounds to incise DNA. The protective effect of rosmarinic acid was further confirmed by the increased expression of OGG1 repair gene, observed through real time RT-PCR. The data obtained is indicative that rosmarinic acid seems to act on the intracellular mechanisms responsible for DNA repair, rather than by a direct effect on reactive oxygen species scavenging, as deducted from the effects observed for luteolin and quercetin. Therefore, these results suggest the importance of these polyphenols, and in particular rosmarinic acid, as protectors of oxidative stress-induced DNA damage that commonly occurs in several pathological conditions, such as neurodegenerative diseases.