A 31-year-old woman with Smith-Magenis syndrome achieved 9.4% weight loss (7.3 kg) and significant behavioral improvements after 10 months of tirzepatide 5 mg weekly. The dual GIP/GLP-1 receptor agonist reduced both her lifelong obesity and aggressive behaviors that had been refractory to standard treatments. This represents the first documented use of tirzepatide in Smith-Magenis syndrome, a rare genetic disorder affecting chromosome 17p11.2 that causes intellectual disability and compulsive eating. The finding suggests these newer obesity medications may offer broader therapeutic potential beyond their established metabolic effects. GLP-1 receptors are abundant in brain regions controlling appetite and behavior, which could explain why tirzepatide addressed both the hyperphagia-driven weight gain and behavioral dysregulation characteristic of this syndrome. While promising, this single case report has obvious limitations—rare genetic syndromes often respond differently than typical populations, and individual responses can vary dramatically. The behavioral improvements, if reproducible, could be transformative for SMS families who often struggle with limited treatment options for aggressive behaviors that complicate daily care.