Objective To investigate the effects of mirtazapine combined with transcranial direct current stimulation (tDCS) on treatment outcomes and levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) in treatment-resistant depression (TRD).Methods A total of 100 TRD patients admitted to Huzhou Third People's Hospital from March 2022 to March 2023 were selected as the study subjects. They were randomly divided into a mirtazapine group (n = 50) and a combined group (n = 50) using the envelope method. The mirtazapine group received mirtazapine alone, while the combined group received mirtazapine in conjunction with tDCS treatment. The post-treatment clinical efficacy, pre- and post-treatment depression severity, sleep quality, quality of life, 5-HT and BDNF levels, and adverse reactions were compared between the two groups.Results The overall effective rate in the combined group was higher than that in the mirtazapine group (P < 0.05). The differences in the pre- and post-treatment scores of Patient Health Questionnaire-9 (PHQ-9) and Pittsburgh Sleep Quality Index (PSQI) in the combined group were higher than those in the mirtazapine group (P < 0.05). The differences in the pre- and post-treatment scores of Generic Quality of Life Inventory-74 (GQOLI-74) in the combined group were higher than those in the mirtazapine group (P < 0.05). The differences in the pre- and post-treatment levels of 5-HT and BDNF in the combined group were higher than those in the mirtazapine group (P < 0.05). The incidence of adverse reactions in the combined group was not significantly different from that in the mirtazapine group (P > 0.05).Conclusion Mirtazapine combined with tDCS has significant effects on the treatment outcomes and levels of 5-HT and BDNF in TRD patients.