Azithromycin, a safe, long-lasting antibiotic that has been trialled as a partner drug for ACTs, is known to kill malaria parasites after 5 days (so called ‘delayed-death’) by targeting their essential remnant plastid ‘the apicoplast’. We have characterised analogues of azithromycin that rapidly kill parasites within one 48hr blood stage lifecycle (termed ‘quick-killing’) at concentrations up to 1500-fold lower than azithromycin, opening up the possibility of developing analogues that induce delayed-death and quick-killing activity in the low nanomolar range. Improved azithromycin analogue activity during 48hr intracellular blood stage growth corresponds to improvements in invasion inhibitory activity, resulting in drugs that broadly and rapidly inhibit throughout the disease causing blood stage lifecycle. Quick-killing activity is effective against multiple Plasmodium spp. and occurs via a secondary mechanism of action, independent of the known apicoplast target. Analogues of azithromycin that achieve significantly increased quick-killing potency (rapid parasite clearance) whilst maintaining activity against the apicoplast (long-term prophylaxis), offer a safe, broad acting next generation anti-malarial for use in combination therapies that would: (i) rapidly clear disease causing parasites, (ii) protect against reinfection and (iii) provide ‘resistance proofing’ through dual mechanisms of action.