Highly efficient and straightforward synthetic routes toward the first total synthesis of 2-(<i>p</i>-hydroxybenzyl)-prodigiosins (<b>2</b>-<b>5</b>), isoheptylprodigiosin (<b>6</b>), and geometric isomers of tambjamine MYP1 ((<i>E</i>/<i>Z</i>)-<b>7</b>) have been developed. The crucial steps involved in these synthetic routes are the construction of methoxy-bipyrrole-carboxaldehydes (MBCs) and a 20-membered macrocyclic core and a regioselective demethylation of MBC analogues. These new synthetic routes enabled us to generate several natural prodiginines <b>24</b>-<b>27</b> in larger quantity. All of the synthesized natural products exhibited potent asexual blood-stage antiplasmodial activity at low nanomolar concentrations against a panel of <i>Plasmodium falciparum</i> parasites, with a great therapeutic index. Notably, prodiginines <b>6</b> and <b>24</b>-<b>27</b> provided curative in vivo efficacy against erythrocytic <i>Plasmodium yoelii</i> at 25 mg/kg × 4 days via oral route in a murine model. No overt clinical toxicity or behavioral change was observed in any mice treated with prodiginines and tambjamines.