People experiencing homelessness (PEH) have a high prevalence of mental illness and substance use disorder (SUD) and substantial acute and chronic disease burden. Transitional care and medical respite programs facilitate a safe transfer for PEH from the acute care to community setting. Many medical respite programs practice harm reduction strategies that can increase the opportunity for positive program outcomes for PEH with SUD. This transitional care and medical respite program evaluation explored program outcomes, health care utilization patterns, and comorbid conditions of persons with and without SUD. People experiencing homelessness with SUD had similar program outcomes and both groups had decreased acute care utilization after program engagement. A high prevalence of trimorbidity, which is associated with early mortality, was noted. Opportunities for harm reduction strategies to promote both social and clinical outcomes are offered.