Turmeric (T) and Bitter Melon leaves (BM) extract has been proven in decreasing melanin contents in in vitro study, but their single extracts effects were lower than the positive control. A study confirmed the combination of plants extracts had melanogenic effect better than the positive control and their single extracts. This study aimed to investigate the anti-hyperpigmentation effect of the combination of T and BM extract on guinea pig skin and compared with the positive control group. This study used a post-test control design. Twenty-five guinea pigs were divided into 5 groups. The negative control group was given by dimethyl sulfoxide; the positive control group was given by a pharma cream that consists of hydroquinone, tretinoin, and fluocinolone acetonide. The combination of extracts was given to experimental groups with doses 500 μg/mL of T and 200 μg/mL of BM; 750 μg/mL of T and 400 μg/mL of BM; 1.000 μg/mL of T and 600 μg/mL of BM, respectively. All groups exposed to UV-B light in 2 minutes/day for 2 weeks. Each experimental group was given 1 ml combination extract once a day for 2 weeks and in the last step, skin biopsies were done. The histopathological examination was conducted by staining with Fontana-Masson and Nuclear Fast Red. The average percentage of melanin area were compared in all group and analyzed with the Kruskal Wallis test followed by Mann-Whitney test with 95% of confidence level. The result showed group-2 and 3 had the better effect than pharma cream.