Background Self-medication with antibiotics (SMA) is a common practise in many parts of Africa, but its magnitude and drivers are not well-known. This systematic review evaluated and compared the prevalence, reasons, sources, and factors associated with of SMA within African sub-regions. Methods An electronic search of PubMed and Google Scholar databases was performed for observational studies conducted between January 2005 and February 2020. Two reviewers independently screened the abstracts and full texts using the PRISMA flowchart and equally performed quality assessment. Both quantitative and qualitative syntheses of selected studies were carried out. Results A total of 40 studies from 19 countries were selected for qualitative synthesis. The prevalence of SMA in Africa ranged from 12.1% to 93.9% with a median prevalence of 55.7% (IQR 41%-75%). Western Africa was the sub-region with the highest prevalence 70.1% (IQR 48.3%-82.1%), followed by Northern Africa with 48.1% (IQR 41.1-64.3%). We identified 27 different antibiotics used for self-medication from 13 different antibiotic classes. Penicillins were the most frequently used antibiotics followed by Tetracyclines and Fluoroquinolones. The most frequent indications for SMA were upper respiratory tract symptoms/infections (27 studies). Common sources of antibiotics used for self-medication were community pharmacies (31 studies), family/friends (20 studies), leftover antibiotics from previous treatments (19 studies), and patent medicine stores (18 studies). Commonly reported factors associated with SMA were no education/ low educational status (9 studies), male gender (5 studies), and low income / unemployment (2 studies). Conclusions The prevalence of SMA in Africa is high and varies across sub-regions with Western Africa having the highest prevalence. Drivers of SMA are complex comprising of socio-economic factors, limited access to healthcare coupled with absence or poorly implemented policies regulating antibiotic sales. Keywords: Self-Medication with Antibiotics, Prevalence, Practices, Associated Factors, Africa