A double‐edged sword! A series of drug hybrids (mannoxanes) have been designed that have the capacity to target Plasmodium falciparum by two distinctive mechanisms. Selected compounds are active at low nanomolar concentrations and outperform artesunate, RKA 182 and a peroxide/amodiaquine combination in terms of curative effects in mice at 10 mg kg−1. Proof of dual mechanism potential is provided by studies on hematin (FeIIIPPIX) dimerisation inhibition and ferrous‐mediated, C‐centred radical production.