Abstract The cathedral of Santa Maria, where the Munoz Chapel is located, is the most remarkable monument of the UNESCO Wold Heritage City of Cuenca (Spain). This emblematic chapel suffers an intense stone weathering by crystallization of a complex mixture of salts including epsomite, hexahydrite, gypsum, chlorides and phosphates. The salt dynamics is controlled by a variable indoor environment with daily and seasonal cyclicality. A methodology combining salt analysis, environmental monitoring and non-destructive stone inspection was adopted in order to understand the salt crystallization dynamics and finally, to design an adapted preventive conservation plan focused on the mitigation of the salt damages. Moreover, new parameters are designed in order to quantify the microenvironmental variability, establishing a new methodology for the analysis of indoor environments. Obtained results reveal that stone weathering is mainly due to: (1) the transformation of both CaSO4 and MgSO4·4H2O into CaSO4·2H2O and MgSO4·6H2O, respectively; and (2) the direct crystallization of MgSO4·6H2O in the porous system. These phases crystallize as efflorescences and as subflorescences, causing granular disintegration, peeling and scaling on the stone. Several preventive measures are finally proposed, being focused on two main objectives: (1) reducing the access of salts and moisture to the monument; and (2) establishing a nonaggressive environment, keeping temperature and relative humidity constants in the range of 15−20 °C and 40–50%, respectively. This proposed climate range is defined in order to avoid both the crystallization of new salts in the porous system of the stone as well as volume changes of the present salts. This study constitutes a pilot project where to test the efficiency of these preventive measures that could be extensive to the whole cathedral complex.