Background: The use of integrase inhibitor-based antiretroviral therapy could be associated with worse weight and metabolic outcomes in patients with HIV infection. Methods: PubMed, EMBASE, and Scopus were searched from inception to March 2022. We selected randomized controlled trials (RCTs) comparing integrase inhibitors with other antiretroviral classes (efavirenz-based or protease inhibitor-based therapies) in naïve HIV patients. Random effects meta-analysis was used to assess the effects of integrase inhibitors vs. controls on weight and lipid outcomes. Effects were described as mean differences (MD) and their 95% confidence intervals (CI). Certain pieces of evidence (CoE) were evaluated using the GRADE methodology. Results: Six RCTs (n = 3521) were included, with patients followed up between 48 and 96 weeks. The use of integrase inhibitors in comparison with other antiretroviral classes was associated with an increase in weight (MD 2.15 kg, 95%CI 1.40 to 2.90, I2= 0%, moderate CoE), and decreases in total cholesterol (MD −13.44 mg/dL, 95%CI −23.49 to −3.39, I2 = 96%, low CoE), LDL cholesterol (MD −1.37 mg/dL, 95%CI −19.24 to −3.50, I2= 83%, low CoE), HDL cholesterol (MD −5.03 mg/dL, 95%CI −10.61 to 0.54, I2= 95%, low CoE), and triglycerides (MD −20.70 mg/dL, 95%CI −37.25 to −4.15, I2= 92%, low CoE). There was a high risk of bias in two RCTs and some concerns about bias in two RCTs. Conclusions: In HIV patients, the use of integrase inhibitor-based therapy in comparison with protease inhibitor- or NNRTI-based therapy was associated with a small increase in weight and small decreases in lipid serum levels.