Abstract Background Corona virus pandemic (COVID 19) has emerged as the single most important topical issue and poses a challenge to medicine. Adolescent school children are exposed to a varying degree. Objectives The study is aimed to determine the knowledge of the mode of spread and preventive practices among college adolescents attending six secondary schools in Enugu metropolis. Methodology This was a cross-sectional study carried out in 6 secondary schools among 500 college adolescents. A pretested, interviewer-administered questionnaire was used for data collection. Results Majority of the respondents, 98.4% were aware of COVID-19. Although, a higher proportion of the respondents, 52.0% were aware COVID-19 could be transmitted through contact with infected persons, only a minor proportion of them, 42.4% had a good knowledge of the mode of spread of COVID-19. However, a high proportion of the respondents, 69.2% practiced good preventive measures against COVID-19. Also, respondents whose parents were self-employed were 1.4 times more likely to have good knowledge of the mode of spread of COVID-19 when compared with those whose parents were on paid employment [adjusted odd ratio (AOR) = 1.4, 95% confidence interval (CI): 0.9–2.0]. The respondents whose fathers have attained tertiary education were 1.6 times more likely to have good preventive practices against COVID-19 when compared with those who had secondary school and below (AOR = 1.6, 95% CI: 1.04–2.5). Conclusion Though college adolescents were aware of COVID-19, not a significant proportion practiced good preventive measures against COVID-19. Knowledge of mode of spread and preventive practices were significantly enhanced by fathers’ educational status and being a female adolescent child.