Abstract Motivation Protein–protein interactions play a fundamental role in biological systems. Accurate detection of protein–protein interaction sites (PPIs) remains a challenge. And, the methods of PPIs prediction based on biological experiments are expensive. Recently, a lot of computation-based methods have been developed and made great progress. However, current computational methods only focus on one form of protein, using only protein spatial conformation or primary sequence. And, the protein’s natural hierarchical structure is ignored. Results In this study, we propose a novel network architecture, HSSPPI, through hierarchical and spatial-sequential modeling of protein for PPIs prediction. In this network, we represent protein as a hierarchical graph, in which a node in the protein is a residue (residue-level graph) and a node in the residue is an atom (atom-level graph). Moreover, we design a spatial-sequential block for capturing complex interaction relationships from spatial and sequential forms of protein. We evaluate HSSPPI on public benchmark datasets and the predicting results outperform the comparative models. This indicates the effectiveness of hierarchical protein modeling and also illustrates that HSSPPI has a strong feature extraction ability by considering spatial and sequential information simultaneously. Availability and implementation The code of HSSPPI is available at https://github.com/biolushuai/Hierarchical-Spatial-Sequential-Modeling-of-Protein.