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Abstract Background The prevalence of depression is increasing in Japan. Pharmacists play an important role in helping patients use medicines effectively. Several studies had investigated the impact of community pharmacists on patient adherence to antidepressant therapy, and their results indicated that further study was warranted. Methods This study was conducted from June 2019 to May 2020 using a cluster non-randomized, open-label, parallel-group design. Four community pharmacy stores in Osaka and Hyogo Prefectures, Japan, participated in the study, and enrolled patients with unipolar depression. In the intervention group (IG), patients received cognitive behavioral therapy (CBT)-based medication support, and their medication adherence and adverse drug reactions were monitored by telephone. In the control group (CG), the pharmacists engaged in routine interactions with the study participants. Before participating in this study, the intervention-group pharmacists attended a 5-hour training session on CBT-based medication support. The primary outcome of this study was medication adherence, assessed using the Drug Attitude Inventory (DAI)-10. Secondary outcomes included the changes from baseline at 6 months in the following variables: the Patient Health Questionnaire (PHQ)-9 total score, the EQ-5D-5 L (Euro-QOL 5 dimensions 5 levels) score, patient satisfaction, and the Pharmacists’ Confidence Scale about Medication Consultation for Depressive Patients (PCMCD) score. Results Four pharmacies (two in IG and two in CG) completed the intervention period. Results were obtained from 19 patients in the IG and 12 patients in the CG. In the IG, the mean DAI-10 score increased from 4.941 at baseline to 6.105, the mean PHQ-9 score decreased from 9.263 to 8.625, and the mean patient satisfaction score increased from 39.947 to 42.211. In the CG, the mean DAI-10 score decreased from 6.333 to 4.167, the mean PHQ-9 score increased from 9.333 to 12.923, and the mean patient satisfaction score decreased from 38.929 to 38.167. Conclusion CBT-based medication support provided by community pharmacists may improve patient medication adherence to antidepressant therapy and symptoms. Such support can be expected to facilitate better treatment of depressed patients and may also allow the duration of treatment to be shortened. Trial registration UMIN000037954, Date of first registration: 17/06/2019.