BACKGROUND Functional dyspepsia (FD) is a relatively common disorder whose pathogenesis has yet been poorly understood. There are still debates concerning definitions and the best possible treatments for this disorder. We aimed to assess the effectiveness of buspirone, a 5-hydroxytryptamine (HT)1A agonist, in improving the symptoms and quality of life (QoL) as well as psychological dimensions in patients with FD. METHODS This study was a randomized, double-blinded, placebo-controlled trial performed on 30 patients with FD, residing in the city of Sari, northern Iran, from December 2017 to October 2018. Consecutive patients referring to a tertiary hospital with a clinical diagnosis of FD, according to the Rome IV criteria, were recruited. All patients were ethnically Persian and had normal upper endoscopy and negative histological evaluation results for any gastrointestinal disease or helicobacter pylori (H. pylori) infection while evaluating biopsy samples endoscopically. Exclusion criteria were being diagnosed with major psychiatric disorders, suicidal thoughts, recent treatments with psychoactive drugs, as well as major cognitive impairments. Patients were randomly assigned to receive either buspirone (n=18) or placebo (n=12) for two months. The first group received buspirone 5mg three times a day for the first month and 10mg three times a day for the second month. During the treatment course, the patients were advised to report any adverse reactions. Also, both groups were evaluated by three questionnaires [demographic characteristics form, the 36-Item Short-Form Health Survey (SF-36), The Short-Form Leeds Dyspepsia Questionnaire (SF-LDQ) and Hospital Anxiety and Depression Scale(HADS)] at the baseline and at the end of the 8th week by a blinded psychologist. Finally, data were analyzed using SPSS software (version 18). P values <0.05 were considered statistically significant. RESULTS The most common symptoms of the patients were FD followed by heartburn. No significant differences were observed between buspirone and placebo groups regarding QoL (p=0.58), anxiety and depression (p =0.36), and severity and frequency of FD symptoms (p =0.22) before and after the intervention. In both groups, the overall QoL as well as HADS and SF-LDQ scores had significantly improved at the end of the study compared with the baseline. CONCLUSION Our findings indicate no significant effects associated with buspirone on the clinical course of FD, compared with placebo. More studies are needed to introduce effective therapies according to the pathophysiology of FD.