Background Little evidence exists regarding the clinical value of synbiotics in the management of post-treatment complications of breast cancer especially breast cancer-related lymphedema (BCRL). This study aimed to investigate the effects of synbiotic supplementation along with calorie restriction on quality of life and edema volume in patients with BCRL. Methods This randomized, placebo-controlled, clinical trial was conducted on 135 overweight and obese women with BCRL aged 18–65 years old. Participants were randomly allocated to receive a calorie-restricted diet plus 10 9 CFU synbiotic supplement (CRS group; n = 45) or placebo (CRP group; n = 45), daily for 10 weeks. Also, a control group (n = 45) with no intervention was included in the trial. All of the participants received Complete Decongestive Therapy for lymphedema treatment. The quality of life score, edema volume and body mass index (BMI) were measured at baseline and end of the trial. Results A total of 121 subjects completed the trial. CRS group showed a significant decrease in the total quality of life score (P = 0.004), and it’s psychosocial ( P = 0.022) and functional ( P = 0.002) domain scores, as well as edema volume ( P = 0.002) and BMI ( P < 0.001) in comparison to the control. However, there were no significant differences in changes in trial outcomes between the CRS and CRP groups. Conclusion Synbiotic supplementation along with a low-calorie diet was effective in quality of life, edema volume, and BMI improvement; mostly due to low-calorie diet. It seems that adding a dietitian consultation on the lymphedema management strategy may provide a better result in lymphedema control.