The aim of conducting a systematic review of the available literature on antibiotic self-medication was to obtain comprehensive data on prevalence, reasons, common antibiotics, self-treated diseases, and drug and information sources of antibiotics used for self-medication worldwide. PubMed, ScienceDirect, SpringerLink, and Taylor & Francis Online were used to perform a comprehensive search on articles published between 2011 and 2020 in the English language. Studies focusing on the prevalence of antibiotic self-medication and its associated factors were included in this review. AXIS Appraisal tool for Cross-sectional studies (AXIS tool) was used for quality assessment of the included articles. A total of 76 studies from diverse geographical locations, including 62668 individuals, were included in this systematic review. The prevalence of SMA in the included studies ranges from 2.6% to 86.5%. Major reasons for non-prescribed use of antibiotics include healthcare costs and time constraints. Respiratory tract infections, fever, and prophylaxis of various symptoms appeared to be prominent self-treated health issues. Pharmacy or superstore, leftovers, and relatives or friends were the most common sources of acquiring antibiotics for self-medication. Similarly, the majority tend to self-medicate with antibiotics based on information obtained from a pharmacy, previous prescription, or personal experience. Self-medication with antibiotics was considered a pervasive issue, with penicillin being the most commonly self-medicated antibiotic. Lack of public awareness and little attention of researchers to not only self-medication but also other related issues such as antibiotic resistance, necessitates the immediate development and execution of public health policies and multifaceted interventions to ensure rational use of antibiotics eventually reducing antibiotic resistance.