Background: Hormonal therapy for menopause has been found to be the most efficacious treatment, but it may be associated with adverse effects in some of the women. Rheum rhaponticum root extract (”ERr 731”), which is available worldwide, is a natural, reliable, effective, and well-tolerated remedy for women in perimenopausal women with menopausal symptoms (MSs), but there is no Indian study demonstrating its efficacy, safety, and tolerability till date. Objective: This study aimed to evaluate the efficacy and safety of ERr 731 in alleviating MSs in perimenopausal Indian women. Patients and Methods: In this open-labeled prospective study, 129 perimenopausal women were treated with tablet containing 4 mg of Rr dried root extract once daily for 12 weeks. The Menopause Rating Scale (MRS) II score, endometrial thickness (ET), blood pressure, glycemic status, lipid profile, and high-sensitivity C-reactive protein (hs-CRP) level were periodically assessed and compared. Results: A significant reduction (67% by 12 th week) in the mean MRS II score was observed from baseline till the end of 12 weeks (18.1; 95% confidence interval [CI]: 17.0–19.2; P < 0.001). A monotonic reduction in the mean total MRS II score over time was found (1.51 units/week; 95% CI: 1.42–1.60 units/week; P < 0.001) noticeable. There was a reduction in the mean ET from baseline till the end of 12 weeks, although the change was not significant. There were significant reductions in the mean fasting (6.3 mg/dl; 95% CI: 1.7–11.0 mg/dl; P = 0.008) and postprandial (6.3 mg/dl; 95% CI: 1.0–11.7; P = 0.021) blood glucose levels and glycated hemoglobin level (0.30%; 95% CI: 0.085–0.520; P = 0.007) at 12 weeks. No significant changes were noted in terms of blood pressure, lipid profile, and hs-CRP level. The drug was found to be safe. Conclusion: ERr 731 was well tolerated and was found to be efficacious and safe in alleviating MSs in Indian perimenopausal women.