Down syndrome (DS) has been associated with cardiovascular, gastrointestinal, and immune-related abnormalities. Several dermatologic conditions, including hidradenitis suppurativa, have also been found to be associated with DS. The objective of this study was to characterize the prevalence, presentation, and unique features of dermatologic disorders associated with DS. Electronic searches of EMBASE (via Ovid), MEDLINE (via Ovid), and Web of Science databases were conducted on December 14, 2020. Observational studies including case reports of patients with DS presenting with concomitant primary dermatologic disorder were included. This systematic review captured 40 observational studies and 99 case reports, including 10 observational studies that examined the prevalence of common skin disorders in patients with DS. The most common dermatologic conditions reported includes atopic dermatitis (8 studies, n=180; 19.7% mean prevalence), hidradenitis suppurativa (15, n=478; 3.2%), ichthyosis (4, n=16; 4.7%), lichen nitidus (6, n=6; 1.1%), psoriasis (21, n=65; 4.8%), alopecia areata (27, n=253; 7.4%), vitiligo (8, n=40; 4.4%), onychomycosis (3, n=198; 24.7%), calcinosis cutis (14, n=15), connective tissue nevi (6, n=6), dermatofibroma (3, n=3), melanoma (3, n=3), syringomas (14, n=182; 21.2%), and elastosis perforans serpiginosa (19, n=24; 0.5%). Our results indicate an increased prevalence of common cutaneous disorders in patients with DS, particularly infectious, inflammatory, autoimmune, and connective tissue conditions. Current guidelines for the screening, general management, and use of systemic immunomodulatory agents in this patient population are lacking. Patients with DS would benefit from screening for dermatologic disorders not otherwise regularly performed for earlier diagnosis and treatment. PROSPERO International Prospective Register of Systematic Reviews CRD42021226295; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=226295.