Homeless adults are at increased risk of latent tuberculosis infection (LTBI), which can lead to active tuberculosis (TB) disease. The purpose of this study was to assess acceptability and feasibility of a six-month, nurse-led, community health worker-partnered short-course treatment (3HP) LTBI adherence model for a high risk, LTBI positive, homeless population. Informed by our community advisory board (CAB) and community-based participatory research principles (CBPR), a qualitative study was undertaken and used focus group discussions to identify perspectives of homeless men and women who had undergone LTBI treatment (N = 11, Mage = 51.2, SD 8.60, range 35–60). Three themes formed, which were engaging and recruiting LTBI intervention participants, delivering an LTBI intervention, and retaining LTBI intervention participants. Within those themes, barriers (e.g., lack of LTBI treatment readiness, substance use, etc.), and facilitators (e.g., LTBI and TB health education, familiarity with homeless population, etc.) were discussed to facilitate program recruitment, program delivery and program retention. These findings provide a greater understanding of how to effectively utilize a nurse-led, Community Health Worker (CHW) intervention delivery method to not only improve 3HP LTBI medication adherence, but also decrease substance use, improve mental health, and decrease unstable housing among this vulnerable population at high risk for active tuberculosis.