Background: Despite variation in the types of COVID-19 vaccines and genetic variation in the SARS-CoV-2 genome, using preventive measures remains the first choice to reduce risks associated with COVID-19 infection. Methods: This cross-sectional study highlights students’ knowledge, attitudes, and practices toward SARS-CoV-2 infection during lockdown. The study was conducted at the Imam Abdulrahman Bin Faisal University (IAU), Eastern Province, Saudi Arabia. Data was collected from 43 male preparatory students via an online self-structured questionnaire. Knowledge level was determined using mean scores, while chi-square and t-tests were performed to detect significant differences between groups. Results: Males aged 17–20 years displayed better knowledge regarding COVID-19 than other groups (t = 2.03, p = 0.049). Most participants recognized the typical symptoms and transmission routes; 93% indicated they viewed social distancing as a crucial preventive measure. Following lockdown, a 1.7-fold increase in the number of participants who believed that mask-wearing was an effective preventive measure was observed; however, 37.2% did not trust this practice. There was a 2.2-fold increase in the number of participants who took part in awareness programs during lockdown. Students’ knowledge increased from 73.2% to 81.5% following the lockdown. Specifically, mean knowledge regarding the role of contaminated tools in disease transmission increased from 33.7% to 75.5%. After lockdown, 58.1% of participants were anxious and afraid of having contact with their colleagues, while 39.5% missed their classes due to anxiety. Two sources of information impacted students’ knowledge following the lockdown: university studies (t = 2.149, p = 0.038) and friends (t = 2.6, p = 0.013). Conclusions: The findings suggest that IAU preparatory-year students have acceptable knowledge, awareness, and attitudes towards COVID-19 infection. The study reflects the impact of media on improvement in preventive measure uptake. Knowledge of the pandemic may increase if health education programs are designed to target students.