In the wake of the COVID-19 pandemic, most U.S. colleges closed their campuses—including residence halls—causing significant disruption to students’ lives. Two waves of data were collected from undergraduate students enrolled at a large U.S. Midwestern university: Wave 1 was a confidential online survey of 4989 randomly sampled undergraduate students collected in January/February 2020; Wave 2 was collected in April/May 2020 following campus closure. Our research aimed to: (1) assess how the COVID-19 related campus closure affected college students’ romantic/sexual relationships, (2) examine students’ past month sexual behaviors prior to the pandemic in comparison with their sexual behaviors during campus closure, and (3) compare participants’ pre-pandemic event-level sexual behaviors with those occurring during campus closure. Of 2137 participants who completed both waves (49.8% women, mean age = 20.9), 2.6% were living at home in Wave 1 compared to 71.0% at Wave 2. Of those in relationships, 14.5% experienced a breakup and 25.3% stayed in their relationship but returned home to different cities. There were no statistically significant differences in participants’ prior month reports of solo masturbation or sending/receiving nude/sexy images between Waves 1 and 2; however, participation in oral, vaginal, and anal sex significantly decreased across waves. Examining participants’ most recent sexual events, Wave 2 sex more often occurred with a cohabiting or relationship partner and was rated as more wanted, emotionally intimate, and orgasmic. Implications for sexual health professionals are discussed.