Glucose-6-phosphate-dehydrogenase (G6PD) deficiency is a heterogenous disorder that may lead to severe hemolytic events with the ingestion of fava beans and exposure to certain drugs. We report the first case of a 65-year-old male with Crohn's disease who developed a hemolytic crisis leading to hospitalization shortly after commencement of upadacitinib. An autoimmune condition was excluded but, as his family history was a positive for G6PD deficiency, very low levels of erythrocyte G6PD were detected. Upadacitinib was immediately discontinued with subsequent resolution of hemolysis. This case highlights the importance of rigorous pharmacological surveillance and suggests the need for further studies to clarify the pathogenetic mechanisms underlying this adverse reaction.