<p>Urban vitality serves as a crucial indicator for evaluating the enhancement and transformation of the human environment within the framework of stock planning. Accurately identifying urban spatial patterns at a human scale and uncovering the spatiotemporal heterogeneity of how urban spatial structure influences urban vitality can provide scientific guidance for fostering vibrant and sustainable urban environments. Leveraging multi-source geospatial big data and a multi-scale geographically weighted regression model, this study integrates three-dimensional space and human perception to construct an urban spatial structure indicator system and reveals the spatiotemporal heterogeneity of the relationship between urban spatial structure and urban vitality across different dimensions. Additionally, it compares variations between weekdays and weekends to capture dynamic changes. The research results indicate that: (1) Urban vitality in Yantai central urban area exhibits a typical core–edge structure with strong spatial autocorrelation, suggesting the absence of an orderly and well-planned spatial framework. (2) The spatial distribution of urban vitality is closely linked to urban spatial structure, with notable differences in the influence of specific spatial structure variables between weekdays and weekends, highlighting the necessity of integrating temporal factors in urban vitality assessments. (3) The effects of spatial structure variables on urban vitality demonstrate spatial attenuation or amplification, emphasizing the importance of adopting a context-sensitive approach that considers both global and local perspectives in urban planning. The research findings serve as a valuable foundation for urban planning and design in Yantai central urban area, aiming to improve the precision and effectiveness of response strategies.</p>