Digital technologies can support designers in balancing architectural heritage conservation and performances using multidisciplinary approaches. Fire safety represents a challenging issue, especially in public historical buildings hosting vulnerable occupants, since heavy modifications are often required to facilitate their evacuation. Digital tools based on evacuation simulation are able to verify the impact of other sustainable, compatible evacuation management and planning approaches, especially considering the use of generic software, which can be used by low-trained technicians according to rapid setups. Nevertheless, simulator reliability should be experimentally verified through case study applications. This work thus offers the experimental verification of a rapid setup-based generic evacuation simulator in the context of a significant case study (the “Omero Museum”, Ancona, Italy), placed in a historic building hosting vulnerable occupants (disabled, elderly, children), thanks to a full-scale evacuation drill. The rapid setup described different vulnerable occupants’ categories according to literature data. Comparisons between drill and simulation results, using consolidated verification indicators, showed the overall reliability of the proposed approach, and thus encourage additional tests in historical buildings. The proposed setup-based simulator could be combined with other digital tools (virtual reality, BIM-related) to provide full support to fire risk and evacuation assessments when vulnerable occupants are present.