Introduction adherence to preventive measures to curb the spread of COVID-19 depends on the people´s knowledge, attitudes and practices (KAP) towards COVID-19. Living in rural areas may be associated with poor KAP towards COVID-19. This study compares the KAP regarding COVID-19 of people living in rural and urban areas in Cameroon. Methods this was a comparative cross-sectional study, using data obtained through an online survey of 1,345 Cameroonians amongst which were 828 urban and 517 rural dwellers. The survey questionnaire consisted of; demographic characteristics, 10 questions on Knowledge, 4 on attitudes and 3 on practices. Data was analyzed using SPSS version 25. Results overall, about two-thirds of participants had correct knowledge of COVID-19. The mean knowledge score for urban dwellers was about twice that of rural dwellers (15.77 ± 5.25 vs 8.86 ± 7.24 respectively, p < 0.001). Furthermore, when compared to people who live in urban areas, rural inhabitants are less optimistic about COVID-19 pandemic in Cameroon (OR = 3.43, P<0.001), less likely to accept a trial vaccine for COVID-19 (OR = 1.14, P<0.05), less likely to avoid going to crowded places (OR = 7.42, P<0.01), less likely to wear face mask outdoor (OR = 11.84, P<0,001), and less likely to practice hand hygiene (OR = 1.13, P<0.05). Conclusion our findings suggest a big gap in COVID-19 related knowledge, attitudes, and practices between rural and urban inhabitants in Cameroon. This highlights the need for increase sensitization of Cameroonians, especially rural dwellers on COVID-19 related knowledge, attitudes and appropriate practices.