Polyaluminum chloride (PAC) is a flocculant commonly used to remove microalgal cells from blooming reservoir. However, some cells exposed to PAC can survive and remain suspended at the surface of eutrophic lakes, potentially reblooming in high-temperature conditions. This study investigated the cellular responses underlying the survival resilience of Microcystis in response to PAC treatment. During cell growth, we observed that exposure to low levels of PAC led to a growth pattern resembling normal conditions, whereas cells exposed to high levels of PAC experienced immediate growth inhibition, followed by cell death. Therefore, we employed RNA sequencing to investigate dynamic gene expression. At the transcriptomic level, 264 distinct genes exhibited differential expression under low PAC exposure, significantly affecting the bacterial secretion system and photosynthesis. Changes in the expression of the photosystem II antenna complex phycobilisome were subsequently reflected in changes in phycocyanin pigment production. Furthermore, we identified 223 unique genes under high PAC exposure. Notably, in type II toxin–antitoxin systems, which serve as a prokaryotic defense mechanism, several toxin genes were expressed at higher levels than antitoxin genes, promoting cell death or apoptosis. These findings bridge a gap in the understanding of cyanobacterial ecotoxicology and environmental responses, potentially enhancing biotechnological and clinical applications.