Background: Emergence of antimalarial drugs and insecticides resistance alarms scientists to develop a safe and effective malaria vaccine. A pre-erythrocytic malaria vaccine called RTS,S has made great strides. Aim: The review was aimed to assess the safety of the candidate malaria vaccine RTS,S with AS01 and AS02 adjuvants using data from Phase I-III randomized controlled clinical trials (RCTs). Methods: This systematic review was conducted based on PRISMA 2020. Regardless of time of publication year, all articles related with safety of RTS,S, RCTs published in the English language were included in the study. The last search of databases, and registry was conducted on 30 May, 2022. Pubmed, Google Scholar, Cochrane Library, Wiley Online Library, and Clinical trials.gov were thoroughly searched for accessible RCTs on the safety of RTS,S malaria vaccine. The studies were screened in three steps: duplicate removal, title and abstract screening, and full-text review. The included studies' bias risk was assessed using the Cochrane risk of bias tool for RCTs. This systematic review is registered at Prospero (registration number: CRD42021285888). The qualitative descriptive findings from the included published studies were reported stratified by clinical trial phases. Findings: A total of thirty-five eligible safety studies were identified. Injection site pain and swelling, febrile convulsion, fever, headache, meningitis, fatigue, gastroenteritis, myalgia, pneumonia, reactogenicity, and anemia were the most commonly reported adverse events. Despite few clinical trials reported serious adverse events, none of them were related to vaccination. Conclusion: Most of the adverse events observed from RTS,S/AS01 and RTS,S/AS02 malaria vaccines were reported in the control group and shared by other vaccines. Hence, the authors concluded that both RTS,S/AS01 and RTS,S/AS02 malaria vaccines are safe.