Microcystis and Aphanizomenon are two toxic cyanobacteria genera, which frequently cause blooms in freshwater lakes. In some cases, succession of these two genera was observed in natural water bodies. Among the diverse factors contributing to such succession of dominant cyanobacterial genera, an allelopathic effect was proposed to be involved after the growth inhibitory effect of several Microcystis species on A. flos-aquae was investigated. However, the response of target species exposed to Microcystis are poorly described. In the present study, we used two toxic cyanobacteria strains, Aphanizomenon flos-aquae (Aph1395) and Microcystis aeruginosa strain 905 (Ma905) as research subjects. Aph1395 was inhibited with a necessarily concentrated culture filtrate of Ma905 (MA905-SPE), and the response of the inhibited Aph1395 cells was explored via non-targeted metabolomic profiling. In total, 3735 features were significantly different in the Aph1395 treated with Ma905-SPE vs. those treated with BG11 medium. Among them, the annotations of 146 differential features were considered to be confident via MS/MS spectrum matching analysis. Based on the reported physiological functions of the annotated differential features, we proposed a putative model that in the growth-inhibited Aph1395, a suite of increased or decreased features with activities in apoptosis, growth inhibition, and stress response processes contributed to, or defended against, the allelopathic effect caused by Ma905. Our findings provide insights into the interaction between the bloom forming cyanobacterial species that share the same ecological environment.