Acanthosis nigricans is characterized by the presence of velvety hyperpigmentation of the skin over the neck and the flexural areas. Regardless of different modalities of treatment, none provides a definite standard cure. This study aims to assess the efficacy of topical 10% salicylic acid compared to 10% urea cream in treating acanthosis nigricans in adolescents. A randomized comparative, double-blind study is conducted on adolescents with acanthosis nigricans of the posterior neck. Treatment efficacy was assessed via a narrowband reflectance spectrophotometer at individual follow-up visits at weeks 2, 4, and 8, while the overall success rates were evaluated by the investigator-assessed and participant-assessed global evaluation scales (IGE and PGE). Acanthosis nigricans scoring chart (ANSC) and adverse effects are also assessed. A total of 39 participants with acanthosis nigricans enrolled and completed the study. Throughout the 8-week period of treatment, the use of 10% salicylic acid demonstrated strong effectiveness in treatment with 14.6 ± 10.6% improvement, while the 10% urea demonstrated 12.5 ± 10.9% improvement. Findings from the overall global evaluation scales were consistent with the results from the narrowband reflectance spectrophotometer. Treatment with 10% salicylic and 10% urea produced no serious local skin adverse reactions. Both medications improve neck hyperpigmentation associated with acanthosis nigricans in adolescents, in which the 10% salicylic acid and 10% urea cream demonstrate similar efficacy and safety profiles. Clinical Trials Registry: TCTR20201123003. Supplementary Information The online version contains supplementary material available at 10.1007/s00403-023-02605-6.