Antiretroviral Treatment (ART) has significantly decreased HIV-related morbidity and mortality among children despite the issue of drug resistance and subsequent treatment failure appearing as a challenge. Different studies have been conducted in Ethiopia regarding the prevalence of first-line ART failure among children but the magnitudes of these studies were inconsistent and had great variability. This review aimed to estimate the pooled prevalence of first line ART failure among children and its association with drug substitution and sex of children among first-line ART users in Ethiopia. The review was conducted using both published and unpublished studies until September 2020 in Ethiopia. MEDLINE, PubMed, Hinari, Web of Science, Google Scholar, Africa journal online (AJOL), Open gray literature, and online repository articles were searched. The quality of individual studies was assessed by Joanna Briggs Institute's (JBI) critical appraisal checklist. The statistical analysis was done by STATA-14 software and a random effect model was used. Heterogeneity was assessed using forest plot Cochrane Q–test and I-squared statistic. Publication bias was checked by using a funnel plot and Egger’s and Begg’s statistical tests. The interpretation was made by an odds ratio and with their respective 95% confidence intervals. The heterogeneity rate was 90% and Begg’s and Egger’s for publication bias were insignificant with p-values of 0.89 and 0.11 respectively. The pooled prevalence of pediatric first line ART failure in Ethiopia was 14.98% (95% CI 11.74, 18.21). Subgroup analysis showed that the highest failure rate was virological (9.13%). Female children had 1.4 times more risk of first-line ART failure (OR = 1.42; 95% CI 1.08, 1.85). First-line ART failure among children in Ethiopia is considerably high. Being female increases the likelihood of facing first line ART failure. More attention should be given to female children.