Background: Diarrhoea is currently the second leading cause of childhood mortality globally, after pneumonia. It accounted for 9% of all under-five deaths which was greater than the mortality arising from malaria, HIV and measles combined. The under-five mortality has continued to spike despite medical intervention protocols.This study was therefore designed to assess Caregivers’ knowledge of environmental sanitation and hygiene practices in the prevention of acute diarrhoea among under-five children in Calabar-South, Cross River State, Nigeria. Materials and method: A Caregiver who met the inclusion criteria was enlisted as respondent from each of the 660 households to give a total of 660 respondents. Structured questionnaires were administered to the respondents to collect data. Answers to the questions were numerically weighted and summed up to breakpoints used in categorising the respondents’ knowledge of environmental sanitation and hygiene practices into poor, fair and good knowledge. Results: Six hundred and fifty (650) respondents completed the interview. Male under-five children were 352 (54.2%) and females 298 (45.8%).Child’s age and male sex were statistically significant predictors of occurrence of childhood diarrhoea. Occurrence of acute diarrhoea in under-five children was greatest among children 13 - 24 months149 (67.1%) and male under-five children 196 (55.7%) compared to female under-five children 131 (44.0%). Occurrence of diarrhoea reduced with improved Caregivers’ knowledge of environmental sanitation and hygiene practices. Occurrence of diarrhoea was also observed to reduce with improved educational status and income of Caregivers.