Introduction: We conducted a systematic review and meta-analysis to evaluate the effects of the 5:2 diet on weight loss and cardiovascular disease (CVD) risk factors in overweight and obese individuals. Methods: Databases (PubMed, The Cochrane Library, Web of Science, Embase) were searched for randomized controlled trials of the intervention effects of the 5:2 diet in overweight and obese individuals. The search period was from database establishment to April 2024. RevMan 5.3 and Stata 14.0 were used for the meta-analysis. Results: A total of 20 articles with 1393 participants were finally included. There were 689 participants in the treatment groups and 704 in the control groups. The meta-analysis showed that the 5:2 diet significantly reduces body weight, body mass index, waist circumference, body fat percentage, hip circumference, fat mass, fat-free mass, low-density lipoprotein, systolic blood pressure, and homeostasis model assessment-insulin resistance levels relative to the control group (p < 0.05). However, there was no significant difference in levels of visceral fat, total cholesterol, triglycerides, high-density lipoprotein, diastolic blood pressure, insulin, fasting blood glucose, glycated hemoglobin A1c, and heart rate. Although there were no serious adverse events in the 5:2 diet group, participants in this group experienced mild physical and psychological side effects during the fasting period, which resolved spontaneously after fasting. Conclusion: The 5:2 diet is effective for weight reduction and amelioration of CVD risk factors in overweight/obesity and is safe and feasible. However, the patient's physical condition during the fasting period should be monitored and timely adjustments should be made accordingly.