Down syndrome is the most common chromosomal disorder and may present with a combination of dysmorphic features, congenital heart disease, and immunological deficiency. The association between Down syndrome and psoriasis is unclear. The prevalence of psoriasis in patients with Down syndrome ranges from 0.5% to 8%. The safety of biologics in the treatment of Down syndrome-related psoriasis is still debated. Down syndrome results in mild immunological abnormalities; consequently, the risk of infectious complications during immunosuppressive therapy might be higher in this group of patients. We report a case of a 33-year-old male, a case of chronic plaque psoriasis, Down syndrome (DS), asthma, and hepatitis B. The patient was started on Calcipotriene 0.005%-betamethasone 0.064% ointment, which failed to control the patient's psoriasis; thus, adalimumab was started. His response to adalimumab was significant, where over 70% improvement of the psoriatic lesions was seen.