The Santo Domingo Diocesan School (Orihuela, SE Spain) is a singular case study that relates air quality monitoring and stone conservation. The monument suffers severe damage due to salt crystallization by rising damp, which is related to the indoor environment dynamics, high groundwater salt content, and microstructure, the building’s porous stone (biocalcarenite). Results revealed that 222Rn concentration in indoor air is low due to the building’s high ventilation rate, despite the medium-low geogenic radon potential in the area. Wavelets analysis showed that ventilation is caused by outdoor and indoor temperature variations and directly affects the 222Rn and CO2 dynamics inside the church. CO2, as well as relative humidity (RH), presented periodicities with intermediate frequencies (5–8 days) related to visits. These RH and temperature (T) variations intensified the salt damage by increasing the frequency of dissolution-crystallization cycles. The mineralogical characterization and geochemical calculations concluded that chlorides (halite and sylvite), sulfates (thenardite, epsomite, hexahydrite and aphthitalite) and nitrates (niter) present from dissolution forms to whiskers and hopper-type morphologies. This indicates high saturation values and, therefore, higher crystallization pressure values within the porous media of the biocalcarenite. On the contrary, the near-equilibrium crystal shape and incongruent precipitation reaction for humberstonite suggest a lower alteration for this salt on the building stone.