To prevent transmission of SARS-CoV-2, the virus that causes COVID-19, colleges and universities have implemented multiple strategies including testing, isolation, quarantine, contact tracing, masking, and vaccination. In April 2021, the Chicago Department of Public Health (CDPH) was notified of a large cluster of students with COVID-19 at an urban university after spring break. A total of 158 cases of COVID-19 were diagnosed among undergraduate students during March 15-May 3, 2021; the majority (114; 72.2%) lived in on-campus dormitories. CDPH evaluated the role of travel and social connections, as well as the potential impact of SARS-CoV-2 variants, on transmission. Among 140 infected students who were interviewed, 89 (63.6%) reported recent travel outside Chicago during spring break, and 57 (40.7%) reported indoor social exposures. At the time of the outbreak, undergraduate-aged persons were largely ineligible for vaccination in Chicago; only three of the students with COVID-19 (1.9%) were fully vaccinated. Whole genome sequencing (WGS) of 104 specimens revealed multiple distinct SARS-CoV-2 lineages, suggesting several nearly simultaneous introductions. Most specimens (66; 63.5%) were B.1.1.222, a lineage not widely detected in Chicago before or after this outbreak. These results demonstrate the potential for COVID-19 outbreaks on university campuses after widespread student travel during breaks, at the beginning of new school terms, and when students participate in indoor social gatherings. To prevent SARS-CoV-2 transmission, colleges and universities should encourage COVID-19 vaccination; discourage unvaccinated students from travel, including during university breaks; implement serial COVID-19 screening among unvaccinated persons after university breaks; encourage masking; and implement universal serial testing for students based on community transmission levels.