Harlequin ichthyosis (HI) is a rare, life-threatening genodermatosis that is characterized by thick, scaly, hyperkeratotic plaques throughout the skin and is typically associated with severe ectropion, eclabium, flexion contractures, and dysplastic ears. HI is thought to be caused by a loss-of-function mutation in the ABCA12 gene. It has traditionally been thought to be difficult to treat, as there are currently no treatments available that are approved by the Food and Drug Administration (FDA). We present a case of a 15-year-old boy with HI and a complex medical history who was treated with a trial of off-label ustekinumab. There was an initial mild improvement in his erythema within one month of treatment, but by his one-year follow-up, ustekinumab had failed to produce a significant treatment response and was, thus, discontinued from his regimen. This case report highlights that although ustekinumab may be a viable treatment option for other ichthyotic entities, more research is needed to evaluate its clinical safety and efficacy in treating pediatric patients with HI.