A systematic review of antibiotic‐resistant Gram‐positive bacteria in Africa from a One Health perspective is lacking. Here, we report result from a search for English‐language articles on the resistance mechanisms and clonality of Gram‐positive bacteria in Africa between 2007 and 2019 reported in PubMed, Web of Science, ScienceDirect, and African Journals OnLine; 172 studies from 22 different African countries were identified. Resistance genes, such as mecA, erm(B), erm(C), tet(M), tet(K), tet(L), vanB, vanA, vanC, and tet(O), were found to be common. Staphylococcus spp., Enterococcus spp., and Streptococcus spp. were the main species reported by the studies, with clones such as Staphylococcus aureus ST5 (n = 218 isolates), ST8 (n = 127 isolates), ST80 (n = 133 isolates), and ST88 (n = 117 isolates), and mobile genetic elements such as IS16 (n = 28 isolates), IS256 (n = 96), Tn916 (n = 107 isolates), and SCCmec (n = 4437 isolates) identified. SCCmec IV (n = 747 isolates) was predominant, followed by SCCmec III (n = 305 isolates), SCCmec II (n = 163 isolates), SCCmec V (n = 135 isolates), and SCCmec I (n = 79 isolates). Resistance to penicillin (n = 5926 isolates), tetracycline (n = 5300 isolates), erythromycin (n = 5151 isolates), rifampicin (n = 3823 isolates), gentamycin (n = 3494 isolates), sulfamethoxazole/trimethoprim (n = 3089 isolates), and ciprofloxacin (n = 2746 isolates) was common in most reports from 22 countries. Clonal dissemination of resistance across countries and between humans, animals, and the environment was observed. Resistance rates ranged from 1.4% to 100% for 15 of the studies; 10 were One Health–related studies. Strict infection control measures, antimicrobial stewardship, and periodic One Health epidemiological surveillance studies are needed to monitor and contain the threat of increasing antibiotic resistance in Africa.