Background: The governments of many countries have taken steps to avert the spread of COVID 19. The gradual relaxation of the lockdown in Nigeria might be counter-productive if not properly managed. The best means to reduce and stop transmission is for the public to be adequately informed about the disease and its preventive measures. This research assessed the knowledge of COVID-19 and practice of preventive measures along with its predictors among Nigerian residents during the ease of the lockdown. Methodology: A cross-sectional study was conducted among 1421 adult residents of Nigeria. Data were collected between 6th and 20th September, 2020, using a semi-structured online questionnaire adapted from previous studies. IBM SPSS version 26 was used for data analysis. Pearson's Chi-square and logistic regression were used to determine the predictors of preventive practices. Results: The mean age of the respondents was 27.5 ± 9.1 years. A very large proportion (98.8%) of the respondents had a good knowledge of the disease (score of ≥4 out of 6 variables) and the internet (70.1%) was the major source of their information. However, only 57.6% of them had good practice of preventive measures of the disease (score of ≥3 out of 4). Predictor of good practice of preventive measure included female sex (adjusted odds ratio [AOR] = 2.626; 95% confidence interval [CI] = 2.078–3.319), being married (AOR = 2.177; 95% CI = 1.568–3.023), and possessing tertiary and postgraduate level of education (AOR = 1.813; 95% CI = 1.082–3.036 and AOR = 2.102; 95% CI = 1.206–3.664, respectively). However, residents in local government headquarters and other villages as well as towns (AOR = 0.541; 95% CI = 0.388–0.756 and AOR = 0.587; 95% CI = 0.350–0.983, respectively) have less likelihood of engaging in good practice of preventive measures. Conclusion: Majority of the research participants had good knowledge of the disease, while about half take part in good preventive practices measures. Predictors of the practice measures included sex, level of education, place of residence, as well as marital status. Therefore, targeted interventions should be directed to the males, those who reside outside the Federal Capital Territory and state capitals, and other high-risk groups as found by this study to reduce the risk of disease contraction during this period.