Abstract Background Even though treatment failure is higher among TB and HIV infected children in a resource-limited setting, there is no prior evidence in general and in the study area in particular. Hence, this study was aimed at determining the half-life time prediction of developing first-line antiretroviral treatment failure and its risk factors among TB and HIV co-infected children. Methods A historical follow-up study was employed among 239 TB and HIV co-infected children from January 2010-December 2020. The data was entered into Epi data version 4.2.2 and exported to STATA 14.0 Software for analysis. The Kaplan-Meier plot was used to estimate the half-life time to develop treatment failure. The required assumption was fulfilled for each predictor variable. Additionally, those variables having a p-value ≤0.25 in the bivariable analysis were fitted into a multivariable Cox-proportional hazards regression model. P-value, < 0.05 was used to declare a significant association. Results A total of 239 TB and HIV co-infected children were involved in this study. The overall half-life time to develop first treatment failure was found to be 101 months, with a total of 1027.8 years’ follow-up period. The incidence rate and proportion of developing first-line treatment failure were 5.5 per 100 PPY (Person-Year) [CI (confidence interval): 3.7, 6.9] 100 PPY and 23.8% (CI; 18.8, 29.7) respectively. Factors such as hemoglobin 10 mg/dl [AHR (Adjusted Hazard Ratio): 3.2 (95% CI: 1.30, 7.73), severe acute malnutrition [AHR: 3.8 (95% CI: 1.51, 79.65), World Health Organization stage IV [AHR: 2.4 (95% CI: 1.15, 4.93)], and cotrimoxazole prophylaxis non user [AHR: 2.3 (95% CI: 1.14, 4.47)] were found to be a risk factor to develop treatment failure. Conclusion In this study, the half-life time to develop first-line treatment failure was found to be very low. In addition, the incidence was found to be very high. The presence of hemoglobin 10 mg/dl, severe acute malnutrition, World Health Organization stage, and non-use of cotrimoxazole prophylaxis were discovered to be risk factors for treatment failure. Further prospective cohort and qualitative studies should be conducted to improve the quality of care in paediatric ART clinics to reduce the incidence or burden of first line treatment failure among TB and HIV co-infected children.