<p>Natural products (NPs) have been pivotal in drug discovery, with over half of approved small-molecule drugs originating directly or indirectly from NPs. With continuous practice, a significant amount of NP-related data has been accumulated, leading to the booming of various NP databases and chemoinformatics analysis. This review aims to examine chemoinformatics studies of the chemical space of NPs, emphasizing their structural characteristics and bioactivities across different source species, chemotypes, environments, and geographical regions. Current databases document over 1.1 million NPs, which display high structural diversity and complexity, frequently with glycosylation and halogenation. NPs exhibit distinct features based on their origins. Marine NPs are larger and more hydrophobic than terrestrial counterparts, while deep-sea and extremophile-derived NPs show novel scaffolds and bioactivities. NPs occupy broader chemical spaces than synthetic compounds, yet discovery rates of novel structures are declining. The limited availability of NPs (only ~ 10% purchasable) and the redundancy in known scaffolds pose major challenges in NP research. Future strategies highlight integrating multidimensional databases, leveraging artificial intelligence for target prediction, and exploring untapped species and extreme environments to uncover unique bioactive compounds. The key findings of chemoinformatics analysis on NPs to date were summarized. This article presents a comprehensive, multidimensional perspective on NP chemical space, contributing to a deeper understanding of NPs and valuable theoretical insights into natural drug discovery.</p>