The Church of the Holy Sepulchre (Church of the Resurrection) is one of the most important historical sites of Christianity. The current Aedicule structure is the result of various construction phases, damages and destructions, reconstructions, and protection interventions, and as such, it serves as an emblematic case study for five-dimensional (5D) modelling. The innovative and interdisciplinary approach adopted for the modelling of the Holy Aedicule of the Church of the Holy Sepulchre utilizes data from the following: (a) architectural documentation: Description of the current form and structure, as well as its evolution through the ages, based on historic documentation; (b) analysis of construction phases: The construction phases were revealed by a ground-penetrating radar (GPR) survey that was implemented within an integrated methodology, which enabled the technique to identify the various interfaces; (c) geometric documentation: Generation of a 3D high-resolution model, through an automated image-based method and through using terrestrial laser scanning; (d) materials documentation: A wide range of analytical and nondestructive techniques have been used in order to characterize the building materials and extract data for fusion in 5D modelling; and (e) 5D modelling: visualization of the historic construction phases of the Holy Aedicule of the Church of the Holy Sepulchre. The integrated modelling which, after the above analysis, includes enhanced information covering all aspects of the Aedicule structure, geometry, and materials and forms the basis for the creation of an innovative tool that induces mixed reality (MR) with the focus on the Aedicule’s structural evolution (time factor—4D) and on its materials (5D).