In Los Angeles County, California, USA, public health surveillance identified 118 mpox cases among persons experiencing homelessness (PEH) during July–September 2022. Age and sex were similar for mpox case-patients among PEH and in the general population. Seventy-one (60%) PEH mpox case-patients were living with HIV, 35 (49%) of them virally suppressed. Hospitalization was required for 21% of case-patients because of severe disease. Sexual contact was likely the primary mode of transmission; 84% of patients reported sexual contact<3 weeks before symptom onset. PEH case-patients lived in shelters, encampments, cars, or on the street, or stayed briefly with friends or family (couch surfed). Some case-patients stayed at multiple locations during the 3-week incubation period. Public health follow-up and contact tracing detected no secondary mpox cases among PEH in congregate shelters or encampments. Equitable efforts should continue to identify, treat, and prevent mpox among PEH, who often experience severe disease.