Five new oxoprotoberberine alkaloids, miliusacunines A–E (1–5), along with nine known compounds, 6–14, were isolated from an acetone extract of the leaves and twigs of Miliusa cuneata. Their structures were elucidated by spectroscopic analysis. All isolated compounds were evaluated for their cytotoxicities against the KB and Vero cell lines and for antimalarial activities against the Plasmodium falciparum strains TM4 and K1 (a sensitive and a multi-drug-resistant strain, respectively). Compound 1 showed in vitro antimalarial activity against the TM4 strain, with an IC50 value of 19.3 ± 3.4 μM, and compound 2 demonstrated significant activity against the K1 strain, with an IC50 value of 10.8 ± 4.1 μM. Both compounds showed no discernible cytotoxicity to the Vero cell line at the concentration levels evaluated.