Disease prevention is operationally defined in this research as the measures taken to avoid contact with disease pathogens. The indicators of disease prevention measures investigated in this study include: the knowledge and practice of regular hand washing, brushing of teeth, care of the nails and general body cleaning. Maintaining regular hand washing, brushing of teeth, care of the nails and general body cleanliness formed the dependent variables investigated while the habitats of urban and rural settings are the independent variables of the study. The study investigated if the habitat divide of urban and rural settings will have influence on students’ knowledge and practice of cleanliness as disease prevention measure. The sample of the study was 140 Senior Secondary School Two (SS2) students from an urban school and another 140 SS2 students from a rural school making a sample total of 280 SS2 students. Questionnaire containing items indicating understanding of the link between cleanliness and disease prevention using the aforementioned indices was the data collection instrument. The instrument was developed by the researchers and pilot tested; PPMCC of 0.83 indicated that the instrument was reliable. One research question and one hypothesis were posited for the study. Mean and standard deviation was used to answer the research question while t-test was used to test the hypothesis at p < 0.05 level of significance. The study revealed that urban participants in comparison to rural participants demonstrated a better understanding of the link of cleanliness to disease prevention and were also better in the practice of cleanliness. It was therefore recommended that rural schools should intensify the teaching of personal hygiene as well as provision of facilities that will encourage personal hygiene.