Objectives To identify the risk factors for neonatal sepsis in Sub-Saharan Africa. Design Systematic review and meta-analysis. Data sources PubMed, Embase, Web of Science, African Index Medicus and ClinicalTrials.gov were searched for observational studies from January 2010 to August 2020. Setting Sub-Saharan Africa, at all levels of healthcare facilities. Participants 'Neonates' (<28 days of age) at risk of developing either clinical and/or laboratory-dependent diagnosis of sepsis. Outcome measures Identification of any risk factors for neonatal sepsis. Results A total of 36 studies with 23 605 patients from secondary or tertiary level of care facilities in 10 countries were included. Six studies were rated as good quality, 8 as fair and 22 as poor. Four studies were omitted in the meta-analysis due to insufficient data. The significant risk factors were resuscitation (OR 2.70, 95% CI 1.36 to 5.35), low birth weight <1.5 kg (OR 3.37, 95% CI 1.59 to 7.13) and 1.5-2.5 kg (OR 1.36, 95% CI 1.01 to 1.83), low Apgar score at the first minute (OR 3.69, 95% CI 2.34 to 5.81) and fifth minute (OR 2.55, 95% CI 1.46 to 4.45), prematurity <37 weeks (OR 1.91, 95% CI 1.27 to 2.86), no crying at birth (OR 3.49, 95% CI 1.42 to 8.55), male sex (OR 1.30, 95% CI 1.01 to 1.67), prolonged labour (OR 1.57, 95% CI 1.08 to 2.27), premature rupture of membranes (OR 2.15, 95% CI 1.34 to 3.47), multiple digital vaginal examinations (OR 2.22, 95% CI 1.27 to 3.89), meconium-stained amniotic fluid (OR 2.72, 95% CI 1.58 to 4.69), intrapartum maternal fever (OR 2.28, 95% CI 1.18 to 4.39), foul-smelling vaginal discharge (OR 3.31, 95% CI 2.16 to 5.09) and low socioeconomic status (OR 1.93, 95% CI 1.11 to 3.35). We found considerable heterogeneity in the meta-analysis of 11 out of 15 identified risk factors. Conclusion Multiple risk factors for neonatal sepsis in Sub-Saharan Africa were identified. We revealed risk factors not listed by the WHO guidelines. The included studies overall had high risk of bias and high heterogeneity and thus, additional research of high quality is needed. PROSPERO registration number CRD42020191067.