The COVID-19 pandemic has impacted freshmen, compromising their mental health, lifestyles, and academic performance. There are few studies that have investigated changes in the health status and lifestyles of freshmen before and after the pandemic. The aims of this study were: (1) to carry out a pre–post-COVID-19 pandemic comparison between two freshmen samples, in order to detect differences in their socio-demographic characteristics and in some clinical variables; (2) to assess the effect of the COVID-19 pandemic on the social and academic lives of the second sample of freshmen. The samples recruited in 2019 and 2022, matched by propensity score procedure (N = 553), were mostly female (57.3% vs. 55.3%); the mean age was 22.9 and 20.9 years, respectively. The freshmen recruited after the pandemic had less psychological distress and substance use than freshmen recruited before the pandemic. Seventy-eight percent of the freshmen stated that the pandemic had an impact on their social relationships. This effect was greater for females and Italian students. Forty-seven percent reported that the pandemic has worsened their academic performance, while 60% stated that pandemic has improved their grades. The results of this study can provide valuable insights into the impact of the pandemic on freshmen, in order to implement interventions to mitigate the consequences of the pandemic in some subgroups of this target population.