Background: This study is an original contribution to the gender-based perspective of measuring knowledge and practice towards COVID-19 among the Saudi population. Objective: This study investigates the existing knowledge of COVID-19 among both genders and its likely use in practice to combat COVID-19. Design and Setting: Cross-sectional study with an online survey and data collected from all the five regions of Saudi Arabia. Participants and Methods: A structured, self-reported validated questionnaire was developed based on the World Health Organization (WHO) general public advice towards COVID-19 prevention. This study has employed snow-ball sampling technique. Sample Size: 627 participants (Male n=343, 54.7%) and (Females n=284, 45.3%). Results: This study has found that women not only carry better knowledge, but their practicing behavior is far better than the male respondents. Females practiced their knowledge of hands hygiene more in comparison to males (86% vs. 80 %, p >0.05). Female respondents were also practicing more about sneezing/coughing into their elbows as compared to males (79% vs. 71%, p < 0.05). Likewise, the practice of knowledge of staying at home to prevent infection (females 98.2% vs males 95.5%, p > 0.05), and (females 83.2% vs. males 81.5%, p > 0.05), respectively. Conclusion: This study shows that women were more compliant with the WHO public health COVID-19 prevention advice than men, which can decrease the chances of COVID-19 infection.