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University life is challenging for students, given the college life adjustment, life stress, career barriers, and career decision-making self-efficacy required. COVID-19 has made this even more complex. This study investigated the relationships among these factors in college students who experienced COVID-19. Data were collected using an online cross-sectional structured survey of 1242 university students from December 2020 to January 2021. Data were analyzed via independent-sample <i>t</i>-tests, one-way ANOVAs, Pearson’s correlation coefficient, multiple regression, and logistic regression, using SPSS. College life adjustment was significantly correlated with life stress (<i>r</i> = −0.255, <i>p</i> < 0.001), career barriers (<i>r</i> = −0.429, <i>p</i> < 0.001), and career decision-making self-efficacy (<i>r</i> = 0.531, <i>p</i> < 0.001). The regression analysis showed that career barriers, career decision-making self-efficacy, and grade level had a total explanatory power of 33.7% for college life adaptation. The logistic regression analysis showed that the odds ratio (OR) of career barriers being low in the group with a high college life adaptation score was 2.045 (<i>p</i> < 0.001), and the OR of career decision-making self-efficacy being high was 4.107 (<i>p</i> < 0.001), as compared to the group with a low score. To increase college students’ adaptation to college life, career support programs that improve career barriers and career decision-making self-efficacy should be developed.