Conventional antidepressants are useful in the treatment of major depressive disorder (MDD) but are limited by their delayed onset of action and lack of adequate therapeutic response in approximately one-third of patients. This has led to a quest for faster-acting and more effective antidepressants. Scopolamine exhibits rapid antidepressant effects when administered intravenously. We report a case of a female with treatment-resistant depression (TRD) who responded to transdermal scopolamine. She had a rapid (within three days) and sustained (119 days) response to transdermal scopolamine. Further research into the use of transdermal scopolamine for the treatment of depression is recommended.