The aim of this study was to evaluate, in vitro, the protective effect of milk thistle and olive purified extracts on cultured keratinocytes, after solar simulator radiation (SSR). For this purpose, immortalized human keratinocytes were pre-incubated for 2h with different concentrations of milk thistle (5, 10, 30 and 50 µg/mL) and olive (5, 50, 100 and 150 µg/mL) purified extracts, and irradiated with increasing doses of SSR (5, 10 and 20 J/cm2). SSR-induced cytotoxicity was measured through cellular vitality analysis using the Trypan blue method and the micronucleus assay-CBMN- test. Substances’ cytotoxicity was analyzed through Trypan blue and MTT assay. Direct DNA damage was assessed by measuring cyclobutane pyrimidine dimers (CPDs) and p53 expression, oxidative stress was evaluated through the consumption of cellular antioxidants (GSH and NADPH) and the production of peroxidated lipid membranes (TBARs). The study substances resulted well tolerated with significant cytoprotective and anti-oxidant properties, being milk thistle dry extract more effective in limiting the direct DNA damage (p< 0.05), and olive extract particularly able to reduce lipid membrane peroxidation and to increase cellular antioxidants (p< 0.05). In conclusion, both study substances can be defined as safe compounds, showing differential cytoprotective and anti-oxidant activities and might represent interesting options for non-melanoma skin cancers chemoprevention.