The south building of Huadong Hospital is a well-known historic building in Shanghai, China. In August 2021, the building was lifted by 1.30 m to correct the subsidence caused by long-term use and to expand the usable space of the building. To ensure structural safety during uplifting of the historic building, a structural health monitoring system is devised to monitor the overall status of the structure and the state of critical components. The structural health monitoring system comprises sensor, data acquisition, and data management systems. The content that is monitored includes vertical displacement, horizontal displacement, inclination, differential settlement, cracks, strains, and acceleration. The overview and uplifting scheme of the historic building are first introduced. The monitoring system’s design and sensor installation are then thoroughly discussed, followed by monitoring data analysis to investigate the state of the structure before and after uplifting. Furthermore, a structural safety assessment based on multisource monitoring data and neural networks is conducted. Huadong Hospital’s south building is currently the largest uplifted historic building in terms of construction area in China. The building’s structural health monitoring system played an exemplary and promoting role in structural health monitoring during uplifting of historic buildings, and it also has referential significance for similar engineering projects.