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Background. Substances mainly khat, alcohol and cigarette are used during pregnancy in Ethiopia. However, to this date, there is no pooled evidence about the burden of adverse neonatal outcomes among the substance users during pregnancy in the country. Methods . Eligible primary studies were accessed from 4 international data bases (Google Scholar, Science Direct, Scopus, and PubMed). The required data were extracted from these studies and then exported to stata version 14 for analysis. Subgroup analyses were conducted for evidence of heterogeneity. Results . A total of 2298 neonates were included from 7 studies. Among these neonates, 530(23.06%) were those whose mothers used substance during pregnancy (exposed group) whereas 1768 neonates were those whose mothers didn’t use substance during pregnancy (controls group). The pooled prevalence of adverse neonatal outcome among the exposed mothers was 38.32% (95% CI: 29.48%, 47.16%; I 2 = 76.3%) whereas it was 16.29% (95% CI: 9.45%, 23.13%) among the controls. Adverse neonatal outcome was most burdensome among cigarette smokers 45.20% (95% CI: 37.68%, 52.73%; I 2 = .00%) when compared with khat chewers 34.00% (95% CI: 20.87%, 47.13%) and alcohol drinkers 38.47% (95% CI: 17.96%, 58.98%). Low birth weight 42.00% (95% CI: 18.01%, 65.99%; I 2 = 91.8%) was the most common adverse birth outcome. Conclusion . It was found that adverse neonatal outcomes were much more burdensome among antenatal substance users than the controls. Therefore, mothers should be enabled to quit using substance before pregnancy. Besides, strict comprehensive screening of every pregnant mother should be made at antenatal care clinics for early identification and management of antenatal substance use.