Platelet 12-lipoxygenase is believed to play a role in cancer and other pathological conditions, such as psoriasis, atherosclerosis and arthritis. The inhibition of 12-LOX is a potential therapeutic approach in the treatment of tumor metastasis. The extracts of Euclea racemosa Murr. ssp. schimperi (A. DC.) F. White (Ebenaceae) obtained by maceration and naphthoquinones isolated from the dichloromethane extract have been investigated for their 12(S)-HETE inhibitory activity using human platelets. At 100 μg/ml, the dichloromethane extract inhibited the formation of 12(S)-HETE by 88.7% and compounds 7-methyljuglone (2), isodiospyrin (3), neodiospyrin (4) and mamegakinone (5), isolated from this extract, exhibited significant activities with IC50 values ranging from 4 to 58 μg/ml (22.2–155.7 μM). Of these the most abundant compound, 7-methyljuglone displayed a potent inhibitory activity with an IC50 value of 4.18 μg/ml (22.2 μM), which was comparable to the positive control baicalein with an IC50 value of 5 μg/ml (18.5 μM). In contrast, 4(S)-shinanolone (1), the reduced form of compound 2, did not show any significant inhibitory activity even at a concentration of 60 μg/ml.