Self-cleaning and hydrophobic treatments based on TiO2 and SiO2 nanoparticles are widely applied for the preservation of cultural heritage materials, to improve their resilience in polluted environments. Excellent results have been obtained on stone materials, but experiments on painted stone surfaces, such as wall paintings and polychrome plasters used in historic buildings, are still limited. In this work, we present a study on the use of water dispersions of TiO2 nanoparticles obtained via sol-gel and organically modified silica (OrMoSil) for cleaning and protective purposes on Lecce stone, a carbonate stone, widely used for its excellent workability but easily attacked by atmospheric agents and pollutants. First, we evaluated the harmlessness of the treatment on Lecce stone through colorimetric tests, water absorption by capillarity and permeability to water vapor. The photocatalytic activity of the TiO2 nanoparticles was assessed by photo-degradation of methyl orange and methylene blue dyes. The dispersion was then applied on painted samples prepared according to ancient recipes to confirm the effectiveness of the cleaning. The proposed TiO2/OrMoSil-based coating can act as a self-cleaning and protective treatment on lithic surfaces to prevent degradation phenomena and preserve the original appearance of the monument.