Uzbekistan inherited a hospital-based health system from the Soviet Union. We explore the health system-related challenges faced during the scale-up of ambulatory (outpatient) treatment for drug-susceptible and drug-resistant tuberculosis (TB) in Karakalpakstan in Uzbekistan. Semi-structured interviews were conducted with key informants of the TB services, the ministries of health and finance, and their TB control partners. Structural challenges and resource needs were both discussed as obstacles to the expansion of ambulatory TB treatment. Respondents stated need for revising the financing mechanisms of the TB services to incentivize referral to ambulatory TB treatment. An increased workload and need for transportation in ambulatory TB care were also pointed out by respondents, given the quickly rising outpatient numbers but per capita financing of outpatient care. Policy makers showed strong interest in good practice examples for financing ambulatory-based management of TB in comparable contexts and in guidance for revising the financing of the TB services in a way that strengthens ambulatory TB treatment. To facilitate changing the model of care, TB control strategies emphasizing ambulatory care in hospital-oriented health systems should anticipate health system support and strengthening needs, and provide a plan of action to resolve both. Addressing both types of needs may require not only involving TB control and health financing actors, but also increasing knowledge about viable and tested financing mechanisms that incentivize the adoption of new models of care for TB.