Here we tested the effects of clinically approved drugs targeting vital cellular receptors and biochemical pathways against Naegleria fowleri. For the first time, our findings revealed that digoxin and procyclidine showed potent amoebicidal effects as no viable trophozoites were observed (>95% kill rate). In view of the devastating nature of this disease and the problems associated with chemotherapy, the present findings offer promising drug-leads for clinical practice. Drugs tested in the present study are FDA approved and should be of potential value in the management of primary amoebic meningoencephalitis.