Malaria is a devastating infectious disease, causing about 241 million cases in 2020, tragically resulting in 627,000 deaths. The disease burden of malaria has increased in recent years, partly due to emerging parasite resistance to current front-line artemisinin-based drug treatments. As a result, new anti-malarial drugs with novel modes of action urgently need to be discovered and developed. A potential source of novel targets for new antimalarials is the stage of the asexual blood cycle when parasites briefly emerge from old red blood cells (RBCs) to rapidly invade new RBCs. Invasive extracellular merozoite stage parasites have a short half-life and drug-like molecules that can delay or prevent invasion would leave the merozoites exposed to rapid destruction by the immune system. To identify new egress and invasion inhibitors we screened the 400-compound Medicines for Malaria Venture Pathogen Box library and discovered dozens of inhibitors. We found using video microscopy of parasites treated with the aryl acetamide inhibitor MMV006833, that the drug did not specifically block invasion but rather a downstream step in which the newly invaded merozoite normally differentiates into an amoeboid, intracellular, ring-stage parasite. Selection of drug resistant parasites followed by whole genome sequencing revealed resistance mutations in the START-domain lipid transfer protein. Both introduction of the START mutations into wildtype parasites that reproduced drug resistance and evidence for the binding of recombinant START to the drug, confirmed this protein is the target. Analogues of MMV006833 that are as potent as artemisinin, have been synthesised indicating START has great potential as a future therapeutic drug target. Ongoing investigation of the drug’s mechanism of action indicates that START may help transfer phospholipids between parasite and RBC membranes after invasion that are essential for growth and development of the young parasite.