Introduction: Seborrhea or oily skin has been one of the most common complaints affecting both men and women physically and psychologically. Chitosan is a biopolymer obtained from the alkaline deacetylation of chitin. Due to its positively charged nature, chitosan can effectively bind to lipids. Therefore, chitosan nanoparticle (CN) formulation may benefit in the reduction of skin sebum. Objective: The aim of this study was to evaluate the efficacy and safety of CN formulation in the reduction of skin sebum. Method: The study was a randomized, double-blinded, placebo-controlled trial in 24 participants aged 18–40 years with clinical seborrhea. Participants were randomly assigned to apply the CN and gum (CN-G) or placebo (gum alone) twice daily for 4 weeks. Sebum level, corneometry, transepidermal water loss (TEWL), and clinical seborrhea grading were evaluated at baseline and week 2 and 4. Results: In the T-zone, sebum levels in the CN-G group were significantly lower than the placebo group at week 4 (p = 0.043), while for the U-zone, sebum levels were not different between groups. There were no statistical differences in corneometry and TEWL at any visit. Although the clinical seborrhea grading in CN-G was lower, it was not significantly different from the placebo. A few cases reported mild and self-limiting scaling and acneiform eruption. Conclusion: The CN-G gel could significantly reduce sebum levels on seborrhea patients with acceptable safety profiles.