Objective: The objective of this study was to appraise the interrelation between overweight/obesity and the safety and efficacy of COVID-19 vaccination by synthesizing the currently available evidence. Methods: A systematic review of published studies on the safety and efficacy of the COVID-19 vaccine in people who were overweight or obese was conducted. Databases including Embase, Medline Epub (Ovid), PsychInfo (Ovid), Web of Science, PubMed, CINAHL, and Google Scholar were searched to identify relevant studies. The databases of the Centers for Disease Control (CDC) and World Health Organization (WHO) were also searched for relevant unpublished and gray literature. Results: Fifteen studies were included in the review. All the included studies used observational study designs; there were ten cohort studies and five cross-sectional studies. The sample size of these studies ranged from 21 to 9,171,524. Thirteen studies reported using BNT162b2 (Pfizer-BioNTech, USA), four reported using ChAdOx-nCov19 (AstraZeneca, U.K), two were reported using CoronaVac (Sinovac, China), and two were reported using mRNA1273 (Moderna, USA). The efficacy and safety of COVID-19 vaccines have been extensively studied in individuals with overweight/obesity. Most studies have shown that the humoral response decreases with increasing BMI. The available evidence does not conclusively indicate that these vaccines are generally safe in this population. Conclusion: While the efficacy of the COVID-19 vaccine may be less than ideal in people who are overweight or obese, it does not mean that obese people should not be vaccinated, as the vaccine can still provide some protection. There is a lack of evidence for conclusions to be drawn about the safety of the vaccine in the population. This study calls on health professionals, policymakers, caregivers, and all other stakeholders to focus on monitoring the possible adverse effects of injections in overweight/obese people.