Background. The COVID-19 pandemic has brought about significant challenges to Ghana’s education system, leading to the closure of schools for months. On 31 May 2020, the government of Ghana took a bold decision based on expert advice to reopen schools for final-year students amid the COVID-19 pandemic. However, data for students’ knowledge, attitudes, and practices towards COVID-19 are limited. We sought to investigate students’ level of knowledge, attitudes, and practices towards COVID-19 at Tamale Technical Institute, Ghana. Methods. A cross-sectional study was conducted among 175 final-year students from June to August 2020. A validated questionnaire adapted from previous studies was distributed to the students in their various classes by the researchers. Data were analysed using descriptive statistics, analysis of variance, and multivariate logistic regression. All analyses were significant at a p value of less than 0.05. Results. The mean age of the study participants was 21.1 years (SD = 2.67), with more males (72.0%) than females participating in the study. The majority (69.7%) of the students trust traditional media sources, i.e., television and radio to receive COVID-19-related information. Awareness about COVID-19 was high (98.3%), and in total, 62.9% (n = 110) had good knowledge, 58.3% (n = 102) had positive attitudes, and 54.9% (n = 96) had good practices towards COVID-19. Factors associated with knowledge were receiving education on COVID-19 (AOR = 0.23; 95% CI: 0.01, 0.55) and mother level of education (AOR = 0.13; 95% CI: 0.02, 0.66). Positive attitudes towards COVID-19 were 63% less likely among students who did not receive education on COVID-19 (AOR = 0.37; 95% CI: 0.15, 0.90). Students who received education on COVID-19 exhibited good practice towards COVID-19 than students who did not receive education on COVID-19 (p = 0.014). Conclusion. Final-year students of Tamale Technical Institute possess good knowledge, attitudes, and practices toward COVID-19. Our findings demonstrate the significant role of health education in improving students’ knowledge, attitudes, and practices towards COVID-19. We recommend continuous and targeted health education to mitigate the widespread misconceptions about COVID-19 through the use of traditional media such as television and radio.