Objectives: Over the last decades, large number of children living with human immunodeficiency virus (HIV) have been successfully enrolled in care and initiated treatment. However, treatment failure is still a major challenge in the track, missing far too many children. National-level evidence on antiretroviral therapy failure and its associated factors among children receiving highly active antiretroviral therapy is required to alleviate this challenge. Methods: PubMed/Medline, EMBASE, CINAHL, Cochrane library, Google, and Google Scholar databases were used to access eligible studies. This meta-analysis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. In addition, Newcastle–Ottawa Scale quality assessment was applied for critical appraisal. Cochran’s Q statistic, funnel asymmetry plot, and Egger’s test were used to assess heterogeneity and publication bias. Random effect model was computed to explore the pooled burden of treatment failure and its associated factors among children living with HIV. Odds ratio with 95% confidence interval was considered to identify associated factors. Result: The overall pooled prevalence of treatment failure among children living with HIV was 16.6%. Whereas virological, immunological, and clinical failure were 4.49%, 5.41%, and 5.71% respectively, where either of parent is deceased (odds ratio = 2.13, 95% confidence interval: 1.4–3.3), opportunistic infection (odds ratio = 1.67, 95% confidence interval: 1.1–2.5), absence of disclosure of status (odds ratio = 1.6, 95% confidence interval: 1.0–2.5), advanced World Health Organization stage (odds ratio = 4.2, 95% confidence interval: 1.6–10.5), and drug substitution (odds ratio = 2.0, 95% CI: 1.5–2.7) were significantly associated factors. Conclusion: The pooled prevalence of treatment failure among children living with HIV in Ethiopia was lower when compared to most African countries. Accordingly, either prevention or early treatment of opportunistic infection and advanced World Health Organization clinical stages, special care for children whose either parents are deceased, advocating disclosure of status, and avoiding drug substitution as much as possible were still needed to prevent treatment failure.