Objective: To investigate the antimalarial activity and toxicity of the crude ethanolic extract of its pericarp both in vitro and in vivo. Methods: The antimalarial activity of Garcinia mangostana (G. mangostana) Linn. extract against 3D7 and K1 Plasmodium falciparum (P. falciparum) clone were assessed using SYBR green I-based assay. A 4-day suppressive test of Plasmodium berghei (P. berghei) infected mouse was performed to investigate in vivo antimalarial activity. Results: The in vitro antimalarial activity was selective (SI > 5) and classified as weak and good to moderate activity against both 3D7 and K1 P. falciparum clones with median IC50 (range) values of 11.12 (10.94-11.29) and 7.54 (6.80-7.68) μg/mL, respectively. The extract was considered non-toxic to mice. The maximum tolerated doses for acute and subacute toxicity in mice were 5 000 and 2 000 mg/kg, respectively. Median (range) parasite density on day 4 of the negative control group (25% Tween-80), mice treated with 250, 500, 1 000, and 2 000 mg/kg body weight of the extract, and 10 mg/kg body weight of chloroquine for 14 d were 12.8 (12.2-13.7), 11.4 (9.49-13.8), 11.6 (9.9-12.5), 11.7 (10.6-12.8), 10.9 (9.4-11.6) and 0 (0-0)% respectively. Parasite density on day 4 in the control group treated with Tween-80 was higher than the groups treated with chloroquine and all dose levels of the extract. Conclusions: G. mangostana Linn. showed weak antimalarial activity of the extract both in vitro and in vivo could be due to limitation of absorption of the active compounds. © 2014 Hainan Medical College.