Artemisinin-based combination therapy (ACT) is the frontline treatment for Plasmodium falciparum malaria. However, the widespread use of ACT has resulted in its decreased effectiveness, especially in Southeast Asia. New antimalarials with novel mechanisms of action are urgently required. Synthetic peroxide antimalarials, known as ozonides, exhibit potent antimalarial activity both in vitro and in vivo. Peroxide antimalarials are thought to act via the generation of reactive free radicals, but the precise targets have not been clearly defined. Here, we used chemical proteomics to investigate the protein alkylation targets of clickable artemisinin and ozonide probes, including an analogue of the ozonide clinical candidate, artefenomel (OZ439). We employed a comprehensive data independent acquisition mass spectrometry (DIA-MS) approach with extensive controls to generate a robust list of over 250 protein alkylation targets for peroxide antimalarials, and identified redox homeostasis proteins as key targets. Parasite redox homeostasis was then confirmed to be perturbed in peroxide-treated parasites using 1) a reporter parasite line expressing a fluorescence-based biosensor comprising a redox-sensitive GFP (roGFP) fused to human glutaredoxin 1, which determines glutathione-dependent redox status of the parasite in real time, and 2) targeted LC-MS-based thiol metabolomics to accurately measure parasite thiol levels (including thiol metabolites, glutathione precursors and oxidised and reduced glutathione) following peroxide treatment. This work shows that peroxide antimalarials disproportionately alkylate proteins involved in redox homeostasis and that disrupted redox processes are involved in the mechanism of action of these important antimalarials.