The marine eukaryotic alga Heterosigma akashiwo (Raphidophyceae) is known for forming ichthyotoxic harmful algal blooms (HABs). In the past 50 years, H. akashiwo blooms have increased, occurring globally in highly eutrophic coastal and estuarine systems. These systems often incur dramatic physicochemical changes, including macronutrient (nitrogen and phosphorus) enrichment and depletion, on short timescales. Here, H. akashiwo cultures grown under nutrient replete, low N and low P growth conditions were examined for changes in biochemical and physiological characteristics in concert with transcriptome sequencing to provide a mechanistic perspective on the metabolic processes involved in responding to N and P stress. There was a marked difference in the overall transcriptional pattern between low N and low P transcriptomes. Both nutrient stresses led to significant changes in the abundance of thousands of contigs related to a wide diversity of metabolic pathways, with limited overlap between the transcriptomic responses to low N and low P. Enriched contigs under low N included many related to nitrogen metabolism, acquisition, and transport. In addition, metabolic modules like photosynthesis and carbohydrate metabolism changed significantly under low N, coincident with treatment-specific changes in photosynthetic efficiency and particulate carbohydrate content. P-specific contigs responsible for P transport and organic P use were more enriched in the low P treatment than in the replete control and low N treatment. These results provide new insight into the genetic mechanisms that distinguish how this HAB species responds to these two common nutrient stresses, and the results can inform future field studies, linking transcriptional patterns to the physiological ecology of H. akashiwo in situ.