Cyanobacteria are a vital component of freshwater phytoplankton, and many species are recognized for their ability to produce toxins and harmful algal blooms (HABs). Nitrogen is an essential element of all the complex macromolecules in algal cells. However, the underlying molecular mechanism of the changes in transcriptomic patterns and physiological responses in response to N starvation is poorly understood. The transcriptomes were generated via RNA-sequencing (RNA-Seq) technology to study the major metabolic pathway under N starvation. The results shed light on the mechanism of toxin production and physiological adaptations in Microcystis aeruginosa (M. aeruginosa). The cell density gradually increased during the first two days then declined over time and was finally stable at (15.50 ± 0.5) × 105 cell mL-1 after 6 days. The chlorophyll-a content and phycocyanin content of M. aeruginosa increased during the first two days and subsequently decreased markedly over time under N starvation. The variable to maximum chlorophyll fluorescence ratio (Fv/Fm ratio) decreased with time under N starvation. Most photosynthesis genes have similarity decreasing trends with growth physiological changes. The microcystins (MCs) levels generally increased first, reaching a peak value with 1.35 pg cell-1 on the fifth day, and then remained roughly constant. The genes involved in N metabolism-related gene expression were upregulated to maintain normal biological activity, while the genes involved in photosynthesis-related gene expression were downregulated to save energy. All genes encoding algae toxin synthesis were upregulated under N starvation. The observed expression patterns demonstrate that all MCs genes respond similarly to MCs production within the cell. Our results indicate the response mechanism of M. aeruginosa under N starvation and provide a comprehensive understanding of N-controlling cyanobacteria and MCs synthesis. Copyright © 2019 Elsevier B.V. All rights reserved.