Sickle cell anemia is a hemoglobinopathy that causes complications such as Vaso-Occlusive Crisis (VOC), stroke, priapism, Acute Chest Syndromes (ACS), and bone infarcts due to blood vessel occlusion, resulting in hypoxia, ischemia, and inflammation. Preventing these incidents improves the quality of life and lowers mortality rates in Sickle Cell Disease (SCD) patients. This systematic review aims to describe the drugs, their mechanisms of action, dosages, changes in hemoglobin parameters, decrease in VOCs, delay the time for the next VOC, decrease in the length of hospital stay, and side effects associated with these drugs. This review adheres to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines. For this review, we searched the PubMed, Google Scholar, and Cochrane databases and screened them for full free texts published in English and studied in humans in the last five years beginning in 2018. Randomized clinical trials (RCT), observational studies, meta-analyses, systemic reviews, and traditional reviews were all included in the search. According to the type of study, quality assessment tools are used, and eight papers are chosen. Full-text articles from these papers are studied, analyzed, and tabulated. We discussed seven interventions that are used to treat sickle cell disease. Voxelotor, crizanlizumab, L-glutamate, long-term blood transfusions, Zinc (Zn), Niprisan®, and Ciklavit* were found to reduce the number and severity of VOC. We discovered that VOCs containing L -glutamate reduced the length of hospitalization. Magnesium (Mg) did not affect the number and severity of VOCs. This review includes a few articles for the study. Future papers on this subject should include a large sample size and many papers. More clinical trials are required to evaluate the dosages and outcomes of using these drugs in combination to prevent VOCs.