The purposes of this cross-sectional study were to determine the knowledge, attitudes, and behaviors about COVID-19 and its vaccination among 313 individuals experiencing homelessness in Italy and to identify the associated factors. A total of 20.5% identified the virus as a causative agent for COVID-19 and 44.2% identified how the SARS-CoV-2 infection wastransmitted. Those living in homeless shelters were more likely to have this knowledge. Concerns about the safety of the COVID-19 vaccine werehigher in those who were younger, with secondary school as the highest level of education, who practiced Christianity, and who did not believe that COVID-19 was a severe disease. A total of 83.9% received the vaccination. Those who were older, who had correct knowledge, whoperceived to be at a higher risk of getting the disease, and who had a lower concern about the vaccine side effects were more likely to have received the vaccination. The primary reasons for accepting the COVID-19 vaccine were that it wasa preventive measure and that it wasmandatory; those unvaccinated indicated, as the main reasons, a fear of side effects and that it wasnot useful. A relationship and communication between healthcare professionals and this hard-to-reach population are needed, with the implementation of educational and information programs.