Membrane bioreactor (MBR) systems are one of the most widely used wastewater treatment processes for various municipal and industrial waste streams. The present study aimed to advance the understanding of ecologically important keystone taxa that play an important role in full-scale MBR systems. A machine-learning (ML) modeling framework based on microbiome data was developed to successfully predict, with an average accuracy of >91.6%, the operational characteristics of three representative full-scale wastewater systems: an MBR, a conventional activated sludge system, and a sequencing batch reactor. ML-based feature-importance analysis identified Ferruginibacter as a keystone organism in the MBR system. The phylogeny and known ecophysiology of members of Ferruginibacter supported their role in metabolizing complex organic polymers (e.g., extracellular polymeric substances) in MBR systems characterized by high concentrations of mixed liquor suspended solids and a high solid retention time. ML regression modeling also revealed temporal patterns of Ferruginibacter in response to water temperature. ML modeling was thus successfully employed in the present study to investigate complex/non-linear relationships between keystone taxa and environmental conditions that cannot be detected using conventional approaches. Overall, our microbiome-data-enabled ML modeling approach represents a methodological advance for identifying keystone taxa and their complex ecological interactions, which has implications for the sustainable and predictive management of MBR systems.