Background: The high comorbidity of migraine and depression is suggestive of shared risk factors or common mechanisms between the two diseases. In individuals with a depressive disorder, there is a high prevalence of altered midbrain raphe (MBR) echogenicity, detectable via transcranial sonography (TCS), that is suggested to be linked with a dysfunction of the serotoninergic system. In patients with migraine, this alteration has seldom been explored in earlier studies, and conclusions are often lacking. Our study aimed to elucidate whether this alteration is specific to migraine and to determine whether it is related with depression. Methods: This study enrolled patients with migraine (n = 100, 72% female) and patients with tension-type headache disorders (TTH) (n = 62, 78.5% female) from a headache clinic. In addition, 79 healthy subjects (79.7% female) were recruited as controls. All participants underwent a standard interview to evaluate headache information and an interview with psychiatrists for depression evaluation. TCS examinations were performed on all participants. Results: Patients with migraine had a higher rate of MBR hypoechogenicity (28%) compared with that of healthy controls (15.2%) and that of patients with TTH (12.9%). In patients with migraine, reduced MBR echogenicity was associated with depressive symptoms assessed using the Hamilton Depression Rating Scale (HAM-D). No association between migraine self-medication and MBR echogenicity was found. Conclusion: Reduced-echoic MBR detected by TCS is prevalent in migraine patients and is associated with depressive symptoms. TCS-detected hypoechogenic MBR abnormality could be an imaging biomarker of depressive symptoms in patients with migraine.