Background The antimelanogenesis effect of topical and oral glutathione has been shown in several in vitro and clinical studies. However, whether combination of topical and oral glutathione is superior to topical or oral monotherapy is unknown. This study aimed to compare the skin‐whitening effect of topical and oral glutathione combination therapy against topical and oral monotherapy. Methods This double‐blind randomized controlled study was done on 46 participants who were divided into two equal groups. Each group received oral placebo and oral glutathione, respectively. All participants were also instructed to apply topical placebo and glutathione to each facial side, respectively. Colorimeter examination was done biweekly using mexameter and chromameter for 8 weeks. One‐way ANOVA test was used to compare the results of all groups. Results The combination group showed significantly lower melanin index (MI) and L* score to placebo (P < 0.05). The mean MI and L* score of the combination group were the highest of all groups. Statistical significance of difference in L* score was reached when the combination group was compared to the oral placebo and topical glutathione group (P < 0.05). Conclusion This study showed that topical and oral glutathione were effective skin‐lightening agents. Furthermore, combination of topical and oral glutathione might be superior to monotherapy.