This case report highlights collaborative efforts undertaken in Knox County, TN to address an identified HIV cluster that began in 2021 and disproportionately impacted people experiencing homelessness and people using drugs intravenously. The Knox County Health Department coordinated response efforts and worked with local government entities, community organizations, federal partner agencies, and the National Health Care for the Homeless Council to identify gaps in services as well as opportunities to partner for improved HIV detection, prevention, and service delivery. The hope is that this case report will provide replicable strategies and lessons learned for other communities.