OBJECTIVE: The objective of this review was to assess and synthesize evidence on the effectiveness and safety of self-management interventions for improving glycemic control and health-related quality of life among adults with type 2 diabetes mellitus (T2DM) in sub-Saharan Africa. INTRODUCTION: There has been a rapid increase in the prevalence of T2DM in sub-Saharan Africa. Lifestyle-related risk factors require self-management strategies, and these must be tailored to the context. Several randomized controlled trials (RCTs) evaluating T2DM self-management interventions in sub-Saharan Africa have been conducted. INCLUSION CRITERIA: This systematic review included RCTs assessing the effectiveness and safety of self-management interventions among adults with T2DM in sub-Saharan Africa, where the self-management intervention matched at least 1 category of the Practical Reviews in Self-Management Support (PRISMS) for long-term conditions taxonomy. METHODS: The following databases were searched from inception until January 14, 2023: MEDLINE (Ovid), PubMed, Embase (Ovid), CINAHL (EBSCOhost), PsycINFO (Ovid), Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), Directory of Open Access Journals, EThOS, and ProQuest Dissertations and Theses (ProQuest). Global Health (EBSCOhost) was searched from inception until June 8, 2021. OpenGrey was searched from inception until its archive date of December 1, 2020. Two independent reviewers conducted title and abstract screening, full-text screening, data extraction, and critical appraisal. Disagreements were resolved through discussion or with a third reviewer. Data synthesis was conducted narratively, followed by meta-analysis where feasible. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for assessing the certainty of evidence was applied. RESULTS: From 2699 records identified, 18 RCTs were included in the systematic review and 14 in the meta-analysis. Interventions included broad self-management education programs, peer support, exercise interventions with education, nutrition education, educational text messaging, and blood glucose self-monitoring support. Only 4 studies received a "yes" response for more than half of the criteria in the standardized JBI critical appraisal tool for RCTs. Compared to the control, self-management interventions did not significantly reduce glycated hemoglobin (HbA1c) levels at 3 months (302 participants, mean difference [MD] -6.0 mmol/mol, 95% CI -17.5, 5.4; very low certainty on GRADE assessment) or 12 months (1504 participants, MD -3.7 mmol/mol, 95% CI -8.2, 0.7; moderate certainty on GRADE assessment). HbA1c was significantly reduced at 6 months (671 participants, MD -8.1 mmol/mol, 95% CI -10.7, -5.4; low certainty on GRADE assessment). Four studies assessed health-related quality of life, but only 1 demonstrated an improvement (2205 participants). Three studies reported no adverse events in relation to the trial interventions (1217 participants), and adverse events were not reported in the remainder of studies. There did not appear to be clinically significant effects on body mass index, lipid profile, or systolic or diastolic blood pressure. The evidence was mixed for weight and waist circumference. CONCLUSIONS: Self-management interventions for adults living with T2DM in sub-Saharan Africa may produce a clinically significant improvement in glycemic control at 6 months, but this may wane in the long term. There was not convincing evidence to indicate a benefit of these interventions on health-related quality of life, but reporting on this outcome measure was limited. There were insufficient data on adverse events to be able to draw conclusions. REVIEW REGISTRATION: PROSPERO CRD42021237506.