Background: The very low-calorie ketogenic diet (VLCKD) has been recently proposed as an appealing nutritional strategy for obesity management. The VLCKD is characterized by a low carbohydrate content (<50 g/day), 1–1.5 g of protein/kg of ideal body weight, 15–30 g of fat/day, and a daily intake of about 500–800 calories. Objectives: The aim of the current document is to suggest a common protocol for VLCKD and to summarize the existing literature on its efficacy in weight management and weight-related comorbidities, as well as the possible side effects. Methods: This document has been prepared in adherence with Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Literature searches, study selection, methodology development, and quality appraisal were performed independently by 2 authors and the data were collated by means of a meta-analysis and narrative synthesis. Results: Of the 645 articles retrieved, 15 studies met the inclusion criteria and were reviewed, revealing 4 main findings. First, the VLCKD was shown to result in a significant weight loss in the short, intermediate, and long terms and improvement in body composition parameters as well as glycemic and lipid profiles. Second, when compared with other weight loss interventions of the same duration, the VLCKD showed a major effect on reduction of body weight, fat mass, waist circumference, total cholesterol and triglyceridemia as well as improved insulin resistance. Third, although the VLCKD also resulted in a significant reduction of glycemia, HbA1c, and LDL cholesterol, these changes were similar to those obtained with other weight loss interventions. Finally, the VLCKD can be considered a safe nutritional approach under a health professional’s supervision since the most common side effects are usually clinically mild and easily to manage and recovery is often spontaneous. Conclusions: The VLCKD can be recommended as an effective dietary treatment for individuals with obesity after considering potential contra-indications and keeping in mind that any dietary treatment has to be personalized. Prospero Registry: The assessment of the efficacy of VLCKD on body weight, body composition, glycemic and lipid parameters in overweight and obese subjects: a meta-analysis (CRD42020205189).