Genomic editing is a group of technologies that scientists have used to alter an organism’s DNA. Of the several genomic editing techniques, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9 (CRISPR-Cas9) is well known. The CRISPR-Cas9 system is faster, cheaper, more accurate, more efficient than other genomic editing methods, and it is an adaptation from bacteria’s immune mechanism. Sickle cell diseases (SCDs) are a group of monogenic diseases, and despite their high prevalence and chronic debilitating nature, they continue to have few therapeutic options available. The aim of this study is to review existing literature and current clinical trials on CRISPR-Cas9 genomic editing as an innovation in the management of sickle cell disease (SCD), as well as the current state of treatment for SCD. For this systematic review, PubMed, Google Scholar, African Journals Online (AJOL), and Clinicaltrial.gov articles published up to 6th October, 2022 were searched. Searches for current clinical trials using CRISPR-Cas9 as intervention were conducted by using the search terms such as sickle cell disease, genomic editing, genetics, novel treatments, hematopoietic stem cell transplantation, gene therapy, and CRISPR-Ca9. Studies cited include meta-analyses, original research, prospective clinical trials, online abstracts, literature reviews, retrospective studies, case series, and scientific meetings. The primary search obtained 27,678 articles. Following a review of titles and abstracts, a total of 32 publications and 6 ongoing clinical trials were included in this systematic review based on the recent evidence-based management of SCD. CRISPR-Cas9 genomic editing stands out as a novel, innovative technology which has the potential to cure SCD in children and adults with minimal side effects. Six clinical trials are ongoing with a huge potential for scaling up to Phases 3 and 4.