COVID-19 infection is associated with oral lesions which may be exacerbated by tobacco smoking or e-cigarette use. This study assessed the oral lesions associated with the use of e-cigarettes, tobacco smoking, and COVID-19 among adolescents and young people in Nigeria. A national survey recruited 11-23-year-old participants from the 36 States of Nigeria and the Federal Capital Territory, Abuja. Data were collected using Survey Monkey. Binary logistic regression analysis was conducted. Statistical significance was set at -value less than 0.05. There were 2870 participants, of which 386 (13.4%) were tobacco smokers, 167 (5.8%) e-cigarette users, and 401 (14.0%) were both e-cigarette and tobacco users; and 344 (12.0%) had ever tested positive to COVID-19. Adolescents and young people who smoked tobacco had more than twice the odds of reporting gingival inflammation, oral ulcers, dry mouth, and changes in taste than those who did not smoke. Those who used e-cigarettes had 1.5 times higher odds of reporting oral lesions. Respondents who had COVID-19 infection had higher odds of reporting gingival inflammation and lower odds of reporting dry mouth than those who did not have COVID-19 infection. These findings were significant, and may help clinicians to screen for tobacco use and COVID-19 among adolescents and young people in Nigeria.