The number and percentage of people in the US dying while homeless has increased in recent years. However, information about the causes of death most prevalent among this population, and about how cause-specific mortality rates may be shifting over time, has been limited to locally specific data. Using a unique data set of 22,143 homeless decedents in twenty-two localities across ten states and Washington, D.C., from the period 2011-20, we found large increases in all-cause and cause-specific homeless mortality rates. The largest increases in cause-specific homeless mortality rates in the ten-year period were for deaths related to drug and alcohol overdose, diabetes, infection, cancer, homicide, and traffic injury. We discuss implications of these results and posit that people experiencing homelessness are systematically excluded from the life-affirming institutions of housing and health care, in an example of mortal systemic exclusion. The findings have important implications for existing local and federal policy approaches to homelessness.