SummaryTo date, the clinical appearance and histological features of multiple minute digitate hyperkeratosis have been well characterized. However, there is no consensus on its treatment. After a comprehensive search of the databases MEDLINE, EMBASE, Web of Science, and the Cochrane Library and Database of Systematic Reviews, we have summarized the available clinical evidence regarding the therapeutic approaches already reported for this entity since its first description in 1967. Additional publications were identified within the references of retrieved papers. Sixty‐five articles have been revised, resulting in a total of 73 compatible cases. The histopathological features and different classifications used through history have also been considered, updating and completing the available knowledge. Ultimately, we propose topical treatment with 5 % 5‐fluorouracil formulated with 10 % salicylic acid as a potential treatment that has been used successfully in a 51‐year‐old woman at our facility. Further research in form of prospective or comparative studies is encouraged for a better conceptualization of the therapeutics of this disease.