The concomitant prevalence of toxic cyanobacteria blooms and plastic pollution in aquatic ecosystems is emerging as a pressing global water pollution dilemma. While toxic cyanobacteria and microplastics (MPs) can each independently exert significant impacts on aquatic biota, the magnitude and trajectory of the combined interactions remains rudimentary. In this study, we evaluated how MPs influences cyanobacterial stress on keystone grazer Daphnia, focusing on population, individual, biochemical and toxicogenomic signatures. We found that toxic Microcystis (TM) adversely affected the fitness of Daphnia populations (intrinsic rate of population increase), and these adverse effects were amplified in the presence of MPs. Through detailed observation, it was ascertained that MPs promoted the ingestion of TM, culminating in enhanced microcystin bioaccumulation. Using the Eco-Evo model, we found that there was potential absence of correlation between the MPs toxicity and the effect size of MPs on the TM. Utilizing gene set enrichment analysis (GSEA), we further identified a marked suppression of molecular pathways and entities crucial to individual growth and development in the TM-MPs consortium compared to exposure to TM alone. The present study provides important insights about the influence of MPs on cyanobacteria toxicity and the prediction the risk of harmful algal blooms in aquatic ecosystems.