Objective. After months of lockdown due to the COVID-19 outbreak, the U.S. postsecondary institutions implemented different instruction approaches to bring their students back for the Fall 2020 semester. Given public health concerns with reopening campuses, the study evaluated the impact of Fall 2020 college reopenings on COVID-19 transmission within the 632 U.S. university counties. Study design. This was a retrospective and observational study. Methods. Bayesian Structural Time-Series (BSTS) models were conducted to investigate the county-level COVID-19 case increases during the first 21 days of Fall 2020. The case increase for each county was estimated by comparing the observed time series (actual daily cases after school reopening) to the BSTS counterfactual time series (predictive daily cases if not reopening during the same time frame). We then employed multilevel models to examine the associations between opening approaches (in-person, online, and hybrid) and county-level COVID-19 case increases within 21 and 42 days after classes began. The multigroup comparison between mask and non-mask required states for these associations were also performed given that the statewide guidelines might moderate the effects of college opening approaches. Results. More than 80% of our university county sample did not experience a significant case increase in Fall 2020. There were no significant relationships between opening approaches and community transmission in both mask and non-mask required states. Only small metropolitan counties and counties with a non-community college or a higher percentage of student population showed significantly positive associations with the case number increase within the first 21-day period of Fall 2020. For the longer 42-day period, the counties with a higher percentage of the student population showed a significant case increase. Conclusion. The overall findings underscored the outcomes of U.S. higher education reopening efforts when the vaccines were still under development in Fall 2020. For individual county results, we invite the college and county level decision-makers to interpret their results by using our web application.