Homelessness is associated with increased acute care utilization and poor healthcare outcomes. This study aims to compare hospital readmission rates among patients experiencing homelessness and patients who are not homeless and assess the impact of different clinical and demographic characteristics on acute care utilization among patients experiencing homelessness. This was a retrospective study of patients encountered in 2018 and 2019 at ChristianaCare Health Systems. The analysis was done in August 2021. The prevalence of major chronic conditions among patients experiencing homelessness (n=1,329) and those not experiencing it (n=143,360) was evaluated. Patients experiencing homelessness were matched with nonhomeless patients using 1:1 propensity score matching. Time-to-event analysis approaches were used to analyze time-to-readmission and 30-day readmission rates. The 30-day readmission rates were 42.8% among patients experiencing homelessness and 19.9% among matched patients not experiencing homelessness. The hazard of 30-day readmission among patients experiencing homelessness was 2.6 (95% CI=1.93, 3.53) times higher than that among the matched nonhomeless cohort. In patients experiencing homelessness, drug use disorder, major depressive disorder, chronic kidney disease, obesity, arthritis, HIV/AIDS, and epilepsy were associated with shortened time to readmission. Moreover, Black racial identity was associated with shortened time to readmission. Patients experiencing homelessness had higher acute care utilization than those not experiencing homelessness. Black racial identity and several comorbidities were associated with increased acute care utilization among patients experiencing homelessness. Efforts to address upstream social determinants of health, destigmatization, and healthcare management accounting for the whole spectrum of clinical comorbidities might be important in promoting the health of people experiencing homelessness.