Permanganate can be scavenged by dissolved organic matter (DOM), which decreases microcystin (MC) removal efficiency, and permanganate attack on cyanobacterial cells can damage cells, resulting in the release of additional MCs. Here, the impact of sequential permanganate doses on MC‐LR removal in the presence of two DOM isolates (terrestrial‐ and algal‐derived) was examined. Although sequential permanganate dosing reduced the competition for permanganate from each DOM isolate, the overall MC removal efficiency was not as high when multiple smaller doses of permanganate were applied compared to one single dose. Potassium permanganate was not observed to lyse Microcystis cells up to 10 mg L−1. Sequential permanganate dosing did not alter the extent of lysis observed for a model bacterium. Mathematical simulations of permanganate oxidation in the presence of DOM suggested that sequential dosing would be most beneficial for enhancing MC‐LR removal when a small portion of highly reactive DOM exists.