The life-cycle of N. fowleri includes a dormant cyst, an amoeboid feeding stage (trophozoite), and a rapidly swimming flagellate. When freshwater conditions are not favorable for growth, N. fowleri exist in the cyst form. The trophozoite of N. fowleri is a thermophile (heat-loving organisms), and survives and reproduces most efficiently at warm temperatures. When food resources are scarce, the trophozoite enters the flagellate form, which swims to another location searching for better food sources. Once food is found, the flagellate turns back into the trophozoite stage.

Only the trophozoite stage is capable of infecting a human. Even in warm or thermally polluted waters, N. fowleri is always found in low numbers in the environment, and N. fowleri infections are extremely rare.