Stone surfaces and façades of historic buildings, due to their predominately outdoor location, suffer from many deterioration factors, including air pollution, soluble salts, relative humidity (RH)/temperature, and biodeterioration, which are the main causes of decay. In particular, the façades of the buildings deteriorate with direct exposure to these factors; deformation and disfiguration of superficial decoration and formation of black crusts are often observed on the stones. The development and application of self-cleaning and protection treatments on historical and architectural stone surfaces could be a significant improvement in the conservation, protection and maintenance of Cultural Heritage. A titanium dioxide nanoparticle has become a promising photocatalytic material, owing to its ability to catalyze the complete degradation of many organic contaminants and environmental factors. In this study, TiO2 nanoparticles, dispersed in an aqueous colloidal suspension, were applied directly to historic marble stone surfaces, by spray-coating, in order to obtain a nanometric film over the stone surface. The study started with an investigation of some properties of TiO2 nanoparticles, to assess the feasibility of the use of TiO2 on historic stone and architectural surfaces. Scanning electron microscopy (SEM) was, coupled with energy dispersive X-ray (EDX) microanalysis, (SEM-EDX), in order to obtain information on coating homogeneity and surface morphology, before and after artificial aging; the activity of the coated surface was evaluated through UV-light exposure, to evaluate photo-induced effects. The changes of molecular structure occurring in treated samples were spectroscopically studied by attenuated total reflection infrared spectroscopy (ATR-FTIR); activity of the hydrophobic property of the coated surface was evaluated by Sterio microscopy, model Zeiss 2010 from Munich, Germany, equipped with photo camera S23 under 80X magnification. The efficacy of the treatments was evaluated through capillary water absorption, and colorimetric measurements, performed to evaluate the optical appearance. Results showed that TiO2 nanoparticles are good candidates for coating applications on historic stone surfaces, where self-cleaning photo-induced effects are well evident; they enhanced the durability of stone surfaces toward UV aging, improved resistance to relative humidity (RH)/temperature and abrasion affect, reduced accumulation of dirt on stone surfaces when left in open air for 6 months, and did not alter the original features.