Depression is a common mental illness in childhood and adolescence, with an incidence of 4%-5%; it can lead to impairments in learning and social functioning. Transcutaneous auricular vagus nerve stimulation (taVNS) is a commonly used method of auricular acupuncture point stimulation, which is regarded as an effective treatment for adults with depression. The aim of this study was to investigate the efficacy and mechanism of taVNS for adolescents with mild to moderate depression. This randomized controlled clinical trial will include 120 patients aged 12-16 years, all of whom are diagnosed with mild to moderate depression. Patients will be randomly assigned to a taVNS group and a drug control group (sertraline hydrochloride) at a ratio of 1:1. Patients will be evaluated using the 17-item Hamilton Depression Scale, Hamilton Anxiety Rating Scale, Self-Rating Depression Scale, Self-Rating Anxiety Scale, and Pittsburgh Sleep Quality Index scores at baseline, as well as at the 2nd, 4th, 6th, 8th, and 12th weeks. To investigate the underlying neural mechanisms of taVNS treatment from the perspective of the default mode network, multimodal magnetic resonance imaging (MRI; i.e., structural MRI [sMRI], resting state MRI [rsMRI], and pseudocontinuous arterial spin-labeled [pcASL] MRI) will be used to compare cerebral images among groups. MRI data will also be collected from 40 healthy volunteers to assess whether the participants exhibit normal development of structural and functional components. Depression is the most common mental disorder in adolescence. Drug treatment can improve depression symptoms; however, the side effects of drug treatments are often severe. This study proposes a simple physiotherapy that aims to treat adolescents with mild to moderate depression. The mechanism of taVNS in the treatment of depression will also be investigated. The results of this study will provide evidence to guide the application of taVNS in adolescents with depression. © 2020 Chinese Medical Association. Pediatric Investigation published by John Wiley & Sons Australia, Ltd on behalf of Futang Research Center of Pediatric Development.