BACKGROUND: Prevention is the best way to manage a pandemic like COVID-19. The World Health Organization has issued public advice to create awareness by providing people knowledge to prevent/protect them from COVID-19. Hence, the present study was planned to assess knowledge of prevention and its practical use amongst samples from the Saudi Arabian population. It can be used to bring awareness among the masses not only in expanding their knowledge about COVID-19 but also on how to enforce a practicing behavior in relation to the prevention of COVID-19. The study is among the pioneer studies on the issue related to knowledge and practice of the prevention of COVID-19 among Saudis and foreign nationals residing in Saudi Arabia. OBJECTIVE: The prime objective of this study is to examine the existence of knowledge among the Saudi and non-Saudi nationals about COVID-19 and its impact on their behavior to practice the protocols to prevent the disastrous infection of COVID-19. This study has also examined how the residents in Saudi Arabia react to the methods and protection measures adopted by the government for their dominions to eradicate the spread of COVID-19. METHODS: The study used a survey-based methodology and data was collected from Saudi nationals as well as expatriates living and working in five different regions of Saudi Arabia. Non-probability snowball sampling was used to reach and select the population of the current study. A self-designed, structured, and validated questionnaire was electronically distributed among the respondents. SPSS version 21 was used to analyze the data of the current study. RESULTS: Out of the 443 respondents, 356 respondents (84%) knew they had to wash their hands for 20 seconds and did this as well, 303 respondents (75%) knew that sneezing or coughing into the arm/elbow can prevent the spread of COVID-19 and were doing this as well, 357 respondents (82%) knew that COVID-19 can be transferred by shaking hands and avoided this, 333 respondents (79%) knew that they had to maintain a safe distance of at least one meter and kept this distance, 315 respondents (76%) knew that touching one’s face can transfer the virus and avoid this, and 414 respondents (95%) knew that staying at home can decrease the chances of getting infected. The relationship between different regions and most of the knowledge-based and practice-based questions was significant (p < 0.05). CONCLUSION: Results reveal that there is a significant relationship between knowledge and practice, but the strength of association is weak. It was found that knowledge and practice of COVID-19 was followed differently in the five regions of Saudi Arabia and the level of education of the respondents influenced their choice of practice to protect themselves from the effects of COVID-19. The study has contributed in the body of literature by examining the inter-relationship between knowledge and practice and their use in prevention of COVID-19 among the Saudi population.