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Herpes simplex virus type 2 (HSV-2) infection is a prevalent, sexually transmitted infection with poorly characterized prevalence in the Middle East and North Africa (MENA) region.This study characterized HSV-2 epidemiology in MENA. HSV-2 reports were systematically reviewed as guided by the Cochrane Collaboration Handbook and findings were reported following PRISMA guidelines. Random-effects meta-analyses and metaregressions were performed to estimate pooled mean outcome measures and to assess predictors of HSV-2 antibody prevalence (seroprevalence), trends in seroprevalence, and between-study heterogeneity. In total, sixty-one overall (133 stratified) HSV-2 seroprevalence measures and two overall (four stratified) proportion measures of HSV-2 detection in laboratory-confirmed genital herpes were extracted from 37 relevant publications. Pooled mean seroprevalence was 5.1% (95% confidence interval [CI]: 3.6%-6.8%) among general populations, 13.3% (95% CI: 8.6%-18.7%) among intermediate-risk populations, 20.6% (95% CI: 5.3%-42.3%) among female sex workers, and 18.3% (95% CI: 3.9%-39.4%) among male sex workers. Compared to Fertile Crescent countries, seroprevalence was 3.39-fold (95% CI: 1.86-6.20) and 3.90-fold (95% CI:1.78-8.57) higher in Maghreb and Horn of Africa countries, respectively. Compared to studies published before 2010, seroprevalence was 1.73-fold (95% CI: 1.00-2.99) higher in studies published after 2015. Pooled mean proportion of HSV-2 detection in genital herpes was 73.8% (95% CI: 42.2%-95.9%). In conclusion, MENA has a lower HSV-2 seroprevalence than other world regions. Yet, 1 in 20 adults is chronically infected, despite conservative prevailing sexual norms. Seroprevalence may also be increasing, unlike other world regions. Findings support the need for expansion of surveillance and monitoring of HSV-2 infection in MENA.