Natural Products (NPs) and their subset Human Metabolites (HMs) are synthesized in living organisms and, due to their biogenic nature, can be used as starting points for drug discovery projects as well as a source of inspiration for designing new chemical libraries. It is therefore of interest to characterize NPs and HMs in relation to other types of molecules relevant for drug discovery. In this study, a comparative analysis of the molecular topologies was carried out for NPs, HMs, drugs from different time periods, clinical candidates and general bioactive compounds. It is shown that the NP and HM sets have the highest percentage of compounds with only one ring system. NPs have also the highest Ring System Complexity (RSC) of the compared datasets, while general bioactive compounds have the largest number of ring systems. The difference in molecular topology between the datasets is independent of the molecular size and lipophilicity. Further analysis of topological descriptors shows that NPs and HMs have a larger proportion of side chain atoms in relation to their size and have a higher proportion of aliphatic carbons (indicating a more three-dimensional shape) than compounds from the other sets.