With the rapid accumulation of microbiome data around the world, numerous computational bioinformatics methods have been developed for pattern mining from such paramount microbiome data. Current microbiome data mining methods, such as gene and species mining, rely heavily on sequence comparison. Most of these methods, however, have a clear trade-off, particularly, when it comes to big-data analytical efficiency and accuracy. Microbiome entities are usually organized in ontology structures, and pattern mining methods that have considered ontology structures could offer advantages in mining efficiency and accuracy. Here, we have summarized the ontology-aware neural network (ONN) as a novel framework for microbiome data mining. We have discussed the applications of ONN in multiple contexts, including gene mining, species mining and microbial community dynamic pattern mining. We have then highlighted one of the most important characteristics of ONN, namely, novel knowledge discovery, which makes ONN a standout among all microbiome data mining methods. Finally, we have provided several applications to showcase the advantage of ONN over other methods in microbiome data mining. In summary, ONN represents a paradigm shift for pattern mining from microbiome data: from traditional machine learning approach to ontology-aware and model-based approach, which has found its broad application scenarios in microbiome data mining.