With the increasing gap between supply and demand of water resources in China, the virtual water has become an indispensable part of regional water resources management system. It is a new research framework to improve the comprehensive utilization efficiency and explore the feasibility of regional integrated management of water resources. This paper calculated the agricultural, industrial, residential, ecological water footprints, and grey water footprints of 17 cities in Shandong Province based on a bottom-up method. Based on the spatio-temporal analysis of water footprints from 2009 to 2018, we explored the spatial autocorrelation characteristics of water footprints using the exploratory spatial data analysis method. Then, we quantified the local impact effect and spatial spillover effect of influencing factors, such as population, economic growth, technological progress, urbanization, and industrial upgrading based on the combination of the panel data STIRPAT model and the spatial Dobbin model. The results show that ① the water footprint of Shandong Province from 2009 to 2018 presented an upward trend with fluctuation. The spatial layout shows the characteristics of the high water footprint in eastern coastal cities and western plain cities but the low water footprint in central mountain cities. ② The water footprint of Shandong Province has a positively spatial autocorrelation. Compared with the geographical locations, the spatial correlation of the water footprint is more affected by the population factor, showing obvious "High-High" aggregation type and "Low-Low" aggregation type. However, this kind of effect from population factor gradually decreases with time. In recent years, the economic factors have become the main influencing factors of the spatial effect of water footprint. ③ Population is an important source of water footprint, and economic growth is the most important factor in promoting water resources competition between regions. Urbanization can alleviate the pressure on water resource demand in local cities. While, the technological progress and industrial upgrading can not only alleviate the pressure of water resources demand in the local cities but also effectively alleviate the pressure of water resources demand in adjacent cities. Therefore, the technological progress and industrial upgrading should be the focus of the regional integrated management strategy of water resources.