Purpose. To determine immunological and virological failure and associated factors among children infected with human immunodeficiency virus receiving antiretroviral treatments at Hawassa University Hospital, Southern Ethiopia. Methods. A hospital-based cross-sectional study was conducted among 273 HIV-infected children from July 1 to December 1, 2019. Data were collected using a structured questionnaire and review of patient records. Blood samples for viral load and CD4 count were collected. Data were analyzed using SPSS version 20. Significance group comparison was done by the Kaplan-Meier log-rank test. The Cox proportional hazard model was used to select significant factors of the variability between groups. Results. A total of 273 children, between the age ranges of 1 to 14 years, were included. Of these, 139 (50.9%) and 134 (49.1%) were males and females, respectively. Children from the rural area were almost five times more vulnerable for virological and immunological failure than those children from the urban area (
AOR
=
4.912
, (1.276-8.815),
P
=
0.032
). The overall viral load suppression was 196 (71.8%) with a good adherence of 226 (82.9%). Nonsuppressed HIV viral load was found to be 77 (28.2%) which had two times more viral load copies (
AOR
=
2.01
, (1.21–2.66),
P
=
0.001
) when compared to those who had suppressed viral load copies. The proportions of children who had immunological nonresponse were 45.6% (21 out of 46), 30.4% (14 out of 46), and 23.9% (11 out of 46) among children with baseline CD4 of <200, 201-500, and >500 cells/μl, respectively. Unimproved outcomes among females were noted for immunological and virological failure in this study (
AOR
=
1.901
, (1.038-3.481),
P
=
0.038
). Conclusion. In conclusion, the highly active antiretroviral treatment appeared highly effective in terms of immunological and virological long-term outcomes. However, viral suppression (71.8%) in our study was far apart from the UNAIDS target of 90% in 2020. For that reason, strengthening adherence counseling and early initiation of HAART is important.