Aim To summarise and describe the burden of serious adverse drug reactions (ADRs) in sub-Saharan Africa (SSA) in the era of antiretroviral therapy. Methods We searched Medline, CINAHL, Africa-Wide Information, Scopus, and Web of Science, without language restriction up to March 2021. We hand-searched reference lists, conference abstracts, and dissertation databases. We included studies reporting proportions of admissions attributed to ADRs, admissions prolonged by ADRs, or in-hospital deaths attributed to ADRs. Two reviewers independently screened studies, reviewed study quality using a previously published tool, and extracted data. We tested for heterogeneity using I2-statistics and summarised study results using medians and interquartile ranges. Subgroup analyses summarised results by study quality, setting, methodology, and population. Results From 1005 unique references identified, we included 15 studies. Median study quality was 7/10; heterogeneity was very high. Median [IQR] proportion of admissions attributed to ADRs was 4.8% [1.5% to 7.0%] (14 studies), and 6.4% [4.0% to 8.4%] in nine active surveillance studies in adults. Two paediatric studies reported the proportion of admissions prolonged by ADRs (0.29% and 0.99%). Three studies reported the proportion of in-hospital deaths attributed to ADRs (2.5%, 13%, and 16%). Antiretroviral and antituberculosis drugs were often implicated in serious ADRs. Conclusion Evidence of the burden of serious ADRs in SSA is patchy and heterogeneous. A few high-quality studies suggest the burden is considerable, and that it reflects the regional impact of the HIV pandemic. Further characterisation of this burden is required, ideally in studies of standardised methodology.