Many deterioration processes are linked to unsuitable microclimatic condition in cultural buildings. One of the most diffused processes is soluble salts crystallization that can be accelerated in masonry structures within specific microclimatic values for different chemical compounds. In this paper, microclimate and efflorescence diffusion were monitored over a one-year period in the Crypt of the Cathedral of Lecce (South Italy). This allowed to relate the microclimate with the efflorescence variation over time. A three-dimensional computational fluid dynamics (CFD) model was then developed to detail the thermo-hygrometric parameters and airflow patterns responsible for salts crystallization and artworks deterioration. Two main conditions were reproduced; one to simulate the current microclimate, which simulations showed to be inadequate for conservation, and the other to search for a more appropriate solution. In both cases, summer and winter conditions were simulated and compared to find a microclimate able to ensure more suitable thermo-hygrometric intervals required by the constituting artworks materials. The results helped to suggest actions to improve maintenance of the Crypt.