Background As the use of antiretroviral therapy (ART) increases, the issue of treatment failure is still a global challenge, particularly in a resource limited settings including Ethiopia. The results of former studies in Ethiopia were highly variable and inconsistent across studies. Thus, this systematic review and meta-analysis intended to provide the pooled estimation of treatment failure and associated factors among children on antiretroviral therapy. Methods We searched international databases (i.e., PubMed, Google Scholar, Web of Science, Ethiopian Universities’ online repository library, Scopus, and the Cochrane Library) during the period of February 30 to April 7, 2021. All identified observational studies reporting the proportion of treatment failure among HIV positive children in Ethiopia were included. Heterogeneity of the studies was checked using I2 test and Cochrane Q test statistics. We run Begg’s regression test to assess publication bias. A random-effects meta-analysis model was performed to estimate the pooled prevalence of treatment failure. Results The estimated pooled prevalence of treatment failure among children in Ethiopia was 12.34 (95%CI: 8.59, 16.10). Subgroup analysis of this review showed that the highest prevalence was observed in Addis Ababa (15.92%), followed by Oromia region (14.47%). Poor ART adherence (AOR = 2.53, CI: 2.03, 4.97), advanced WHO clinical staging (AOR = 1.66, CI: 1.24, 3.21), and opportunistic infections (AOR = 2.64 CI: 2.19, 4.31 were found to be significantly associated factors with childhood treatment failure. Conclusions This study revealed that treatment failure among children on ART was high in Ethiopia. Poor ART adherence, advanced WHO clinical staging, opportunistic infections, and low level of CD4 cell counts increased the risk of treatment failure.

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