Objective The study objective was to examine the association between phentermine/topiramate therapy and weight loss and adverse events in adults with overweight or obesity by meta‐analysis and systematic review. Methods Medical Subject Headings and free‐text terms were selected to search for eligible trials in PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase up to April 18, 2020. The quality of randomized controlled trials was evaluated by the Cochrane risk‐of‐bias tool. Meta‐analysis was performed using random‐effect models. Results Phentermine/topiramate therapy resulted in an average weight loss of 7.73 kg (95% CI: 6.60‐8.85) in general compared with placebo. The weight loss was related to the dose of phentermine/topiramate. Compared with placebo, the average weight loss was 3.55 kg (95% CI: 2.22‐4.88) for 3.75/23 mg, 7.27 kg (95% CI: 6.40‐8.13) for 7.5/46 mg, and 8.25 kg (95% CI: 6.92‐9.79) for 15/92 mg. For phentermine/topiramate participants in different weight‐loss subgroups, the weight loss of participants with ≥5%, ≥10%, and ≥15% baseline weight loss was 3.18 (95% CI: 2.75‐3.67), 5.32 (95% CI: 4.53‐6.25), and 5.65 (95% CI: 3.55‐9.01), respectively. Compared with placebo, the adverse events associated with the treatment mainly included dysgeusia (odds ratio OR = 8.86, 95% CI: 5.65‐13.89), paresthesia (OR = 8.51, 95% CI: 6.20‐11.67), dry mouth (OR = 6.71, 95% CI: 5.03‐8.94), disturbance in attention (OR = 4.48, 95% CI: 2.39‐8.41), irritability (OR = 4.10, 95% CI: 2.29‐7.33), hypoesthesia (OR = 3.81, 95% CI: 1.32‐11.00), constipation (OR = 2.43, 95% CI: 2.02‐2.93), and dizziness (OR = 2.26, 95% CI: 1.72‐2.98). Phentermine/topiramate also reduced waist circumference, blood pressure, blood sugar levels, and lipid levels. Conclusions Phentermine/topiramate has considerable benefit in reducing body weight, and the efficacy was closely related to the dosage. However, it increased the risk of nervous system‐related adverse events.