The fresco of the Corbii de Piatră Cave Church, dating from the end of the 13th century and the beginning of the 14th century, is applied to the sandstone wall. The degradation of the fresco on large surfaces, with many areas of detachment, has been determined by the infiltration of meteoric water through the sandstone wall on which it is applied, as well as temperature variations, and repeated wetting/drying processes. However, there are small portions of fresco that show good adhesion to the wall. The present research, aimed at providing scientific data to restorers and historians, involves the advanced characterization of a fragment of fresco with good adhesion to the wall and is being carried out by an interdisciplinary team. The stratigraphy, microstructure, compaction defects, chemical composition, and variation of chemical composition in the fresco from the pictorial surface to the mortar-sandstone interface were determined. Correlations were established between degradation processes and wall adhesion.