Objective: To describe a case of a patient diagnosed with major depressive disorder whose trigeminal neuralgia was unexpectedly but rapidly and efficiently responsive to duloxetine. Case Summary: A 37-year-old woman was diagnosed with trigeminal neuralgia, and the initial treatment with carbamazepine 800 mg/d did not improve her pain. In the following 3 years, she was poorly responsive to the combination therapy with several medications, including carbamazepine, valproate, baclofen, diclofenac, and acetaminophen. The repeated gamma knife radiosurgery still did not relieve her symptoms. She developed clinically significant depressive symptoms, and a diagnosis of major depressive disorder was made. Duloxetine 30 mg/d was initiated for the management of depression, with the dose gradually increased to 60 mg/d. Unexpectedly, at the dose of 60 mg/d, the patient reported remarkable relief in her trigeminal neuralgia within the first week. Her depressed mood gradually improved in the following 3 weeks. At the 4-year follow-up, she was gradually tapered off her medications, and her depression and trigeminal neuralgia were well managed on duloxetine 60 mg/d and carbamazepine 600 mg/d. Discussion: The mechanisms may be related to duloxetine’s ability to modulate norepinephrine and serotonin and antagonize N-methyl-d-aspartate (NMDA) receptors. The ignition hypothesis is a proposed etiology of trigeminal neuralgia, in that any individual hyperexcitable neuron can spread its discharge quickly to activate the entire population of neurons. We suggest that duloxetine exerts desynchronizing effects through its NMDA antagonism, modulating the hyperexcitable state of the trigeminal afferents. Conclusions: Duloxetine may be an adjuvant in treatment-resistant trigeminal neuralgia.