Objective To systematically review the efficacy and safety of a very low-calorie ketogenic diet (VLCKD) in patients who were overweight or obese. Methods From inception to August 2021, the electronic databases PubMed, EMbase, Web of Science, The Cochrane Library, CNKI, WanFang Data, VIP, and CBM were searched for randomized controlled trials (RCTs) of VLCKD in patients with overweight or obesity. Two reviewers independently screened the literature, extracted data, and evaluated the risk of bias of the included studies. Then, meta-analysis was performed using Stata 16.0 software. Results A total of 5 RCTs involving 245 patients were included. Among patients with baseline body mass index (BMI) ≥30 kg/m2, the meta-analysis showed that compared with the control group, VLCKD could significantly reduce the BMI (MD=−0.24, 95%CI −0.39 to −0.08, P<0.05), weight (MD=−7.00, 95%CI −10.48 to −3.53, P<0.05) and waist circumference (MD=−7.40, 95%CI −12.68 to −2.12, P<0.05) . The subgroup analysis results showed that compared with the control diet, VLCKD could significantly reduce the glucose (MD=−9.60, 95%CI −17.52 to −1.69, P<0.05), glycated hemoglobin (MD=−0.24, 95%CI −0.39 to −0.08, P<0.05), insulin resistance index (MD=−0.90, 95%CI −1.08 to −0.73, P<0.05) and triglycerides (MD=−41.42, 95%CI −53.78, −29.06, P<0.05) in patients with type 2 diabetes and with obesity or overweight. In patients with obesity or overweight, VLCKD could increase high-density lipoprotein cholesterol (MD=8.60, 95%CI 0.17 to 17.03, P<0.05) when the intervention lasted longer than 12 months. In patients with obesity or overweight, VLCKD had no effect on insulin, total cholesterol, low-density lipoprotein, urea, creatinine, or uric acid. Patients with VLCKD had a higher rate of adverse events than those in the control groups; however, there was no significant difference in the rate when the intervention lasted longer than 4 months. Conclusion The current evidence shows that VLCKD can reduce BMI, weight, and waist circumference and reduce fasting glucose, HbA1c, insulin resistance index, and triglycerides among patients with type 2 diabetes and with obesity or overweight. However, VLCKD has no effect on insulin, total cholesterol, low-density lipoprotein, urea, creatinine, or uric acid. Due to the limited quantity and quality of the included studies, more high-quality studies are needed to verify the above conclusion.