: Interventions that simultaneously target depression and antiretroviral therapy (ART) medication adherence are recommended for improving HIV treatment outcomes and quality of life for adolescents living with HIV. However, evidence is scarce on culturally feasible and acceptable interventions that can be implemented for HIV-positive adolescents in Tanzania. We, therefore, developed a manualized brief psychological intervention that utilizes evidence-based strategies to address depression and ART adherence in adolescents living with HIV in Tanzania. : We used the Theory of Change Enhanced Medical Research Council framework (TOCMRC) for developing complex interventions in health care to develop the intervention in five phases. First, the literature was reviewed to identify potential intervention components. Second, we conducted a situational analysis using qualitative interviews with adolescents living with HIV, health care providers, and caregivers. Third, we conducted a mental health expert workshop; and fourth, theory of change workshops with representatives from the Ministry of Health, mental health professionals, HIV implementing partners, adolescents, and healthcare providers. Lastly, we synthesized results to finalize the intervention and a theory of change map showing the causal pathway for how we expect the developed intervention to achieve its impact. Adolescents living with HIV in Tanzania experience several unmet mental health needs ranging from overwhelming depressive symptoms to not feeling understood by healthcare providers who lack mental health knowledge. Participants perceived psychological intervention that utilizes a task-shifting approach to be acceptable and beneficial to addressing those problems. The novel components of the NITUE intervention included incorporating evidence-based intervention components, namely, cognitive-behavioral therapy, motivational interviewing, and problem solving. In addition, caregiver inclusion in the treatment was essential to ensure access to care, compliance, and improved outcomes. A culturally appropriate brief psychological intervention that utilizes a task-shifting approach to address depression and medication adherence for adolescents living with HIV in Dar es Salaam, Tanzania, was developed. The intervention will be piloted for appropriateness, feasibility, and acceptability and will provide material for a future trial to determine its effectiveness.