This paper illustrates a multidisciplinary approach aimed at the vulnerability assessment of historic masonry heritage in Venice, focusing on questions of method and practice, which specifically involve the disciplines of restoration, building archaeology and structural engineering. Taking into account the existing standards for the management and assessment of cultural heritage, an integrated methodology is proposed for analyzing and interpreting historic constructions. Particular reference is made to Venetian scenery and its relationship with water, from the worldwide known high tide phenomena to the new perspectives offered by MOSE (i.e., Experimental Electromechanical Module, a system of a series of retractable mobile gates) and the new challenges due to climate change. Within such an approach, the different disciplines, including the building archeology, contribute to obtaining an interpretative model for historic buildings subjected to the high tide phenomena, with the aim of performing a vulnerability assessment and to design possible restoration interventions. The proposed methodology is applied to the case study of a Venetian historic palace facing the Grand Canal. For this palace, all the steps of the knowledge path have been carried out, from historical study to geometrical, Material-Constructive Survey, Crack Pattern and Degradation Analysis to stratigraphic analysis. The interpretative model obtained at the end of this path is enriched with the results of preliminary numerical analyses that investigate, in greater depth, the effects of high water phenomena on the rising damp front in masonry walls. Some previsions on the effects of MOSE activation and of climatic change, in particular in terms of sea-level rise, are presented.