Fusarihexins C-E, a group of cyclodepsipeptides that contain a characteristic 2-hydroxy-4-methyl-pentanoic acid (HICA) residue, were recently isolated from the endophytic fungus Fusarium sp. The absolute stereochemistry of HICA was determined to be R in fusarihexin C using a modified Mosher's method. It was assumed that HICA in fusarihexins D and E would have the same configuration, as they are derived from the same biological source. Herein, we report the first total synthesis of the proposed structures of fusarihexins D and E as well as three new analogues. The compounds were synthesized by employing solid phase peptide synthesis (SPPS) and high dilution macrolactamization and characterized by NMR spectroscopy and high-resolution mass spectrometry (HRMS). Comparing the 1H and 13C NMR spectra of synthesized and natural compounds revealed that the HICA residue has the S-configuration in fusarihexin D. The antiplasmodium activity on Plasmodium falciparum and antitumor activity against MCF7 and A431 cells were also investigated. Encouragingly, fusarihexin D (with S-HICA) displayed potent antiplasmodium activity by interfering with the ring stage of the Plasmodium falciparum parasite life cycle (IC50 at 650 nM).