Application of algicidal bacteria is a promising and environmentally friendly way to control cyanobacterial blooms. Lytic effects of the algicidal bacteria on Microcystis aeruginosa have been observed, but the interactions between algicidal bacteria and the cyanobacteria are still elusive. An algicidal bacterium Bacillus sp. B50 isolated from Lake Donghu showed a highly lytic efficiency on M. aeruginosa NIES-843 through heat-resistant extracellular substances from strain B50. The cell density of strain B50 could be maintained at high levels during the lytic process in bacteria–Microcystis system with inoculation densities of 1.9 × 106 and 1.9 × 107 cfu/mL, resulting in the death of M. aeruginosa NIES-843. However, the population dynamics of strain B50 was a bell-shaped curve at low inoculation densities and no lytic effect could be observed. Results of physiological responses suggested that the lytic efficiency may be mediated through inhibition of metabolism and production of reactive oxygen species.