Urban waterfronts are important gateways that reflect a city’s image and characteristics. Evaluating waterfront vitality and its influencing factors is critical for guiding urban waterfront planning and redevelopment. Hourly human movement data, provided by the Baidu Heatmap, were used to explore the weekday and weekend urban vitality spatial distribution characteristics of the waterfronts of the Qinhuai River in Nanjing. Global (ordinary least squares) and local (multiscale geographically weighted regression) models revealed the influence of physical–environmental characteristics (objective) and spatial experience evaluation factors (subjective) on urban vitality. (1) The Qinhuai River waterfront urban vitality agglomeration characteristics were similar between weekdays and weekends, and the core vitality areas were distributed in the dense tourism, commercial, and residential areas along the river. (2) The evaluation of catering experience had the strongest positive correlation with vitality, whereas the waterfront distance had the strongest negative correlation. (3) The influence of each factor on waterfront vitality in the study area exhibited considerable spatial differences, with attenuation trends observed from the east-to-west river sections. This study shows the urban vitality distribution characteristics of the Qinhuai River waterfront spaces. Exploring the influence of physical–environmental and spatial evaluation factors on the vitality distribution can provide a scientific basis and reference for urban waterfront planning and redevelopment focusing on cultivating vitality.