Introduction: Unintentional chemical poisoning contributes significantly to under-five morbidity, mortality, and disability with an incidence rate of 442/100,000 children age 0-5 years, in low-and middle-income countries. Unintentional ingestion of harmful chemicals by under-five children can be prevented if some risk factors that predispose under-five children to unintentional chemical poisoning are modified. The aim of this study is to determine the risk of unintentional ingestion of harmful chemicals among under-five children in Calabar South Local Government Area (LGA) of Cross River State. Materials and Methods: Analytic epidemiology (case-control) design was employed in this study, 120 under-five children living with their parents in Calabar South LGA, Cross River State, were recruited through the use of multistage and simple random sampling technique by balloting. A structured questionnaire was used for data collection after being validated and its reliability tested. Cases were matched with controls using frequency matching. Multivariate analysis in the binary logistic regression model was used to test the hypotheses. Results: The result revealed that underfive children in Calabar South LGA, below 25 months of age are 2 times more likely to have unintentional ingestion of harmful chemicals (odds ratio [OR] = 2.786, P = 0.032). Under-five children under the care of a mother/caregiver below 36 years of age are 1.654 times more likely to experience unintentional ingestion of harmful chemical (OR = 1.654, P = 0.026). Under-five children who are under the care of a mother/caregiver without any formal educational attainment are 2 times more likely to experience unintentional ingestion of harmful chemical (OR = 2.000, P = 0.040). Under-five children residing in non-confortable apartments with their mothers/caregivers are 2 times more likely to experience unintentional ingestion of harmful chemicals (OR = 2.707, P = 0.043). Under-five children whose mothers/caregivers have no designated place where chemicals are kept are 2 times more likely to have unintentional ingestion of harmful chemicals (OR = 2.281, P = 0.040). Under-five children are 5 times more likely to have unintentional ingestion of harmful chemicals when the container of the chemical has no airtight/child-resistant cover on it (OR = 5.364, P = 0.041). Household cleaning agents were the most ingested chemical substances (25.0%) among under-five children in Calabar South LGA, Cross River State. Conclusion: Based on the findings, the researcher recommended that mothers/caregivers of under-five children should take more preventive measures in keeping household cleaning agents and other harmful chemical substances away from the reach of the under-five child. Furthermore, all household chemicals should be airtight/properly covered to avoid under-five children gaining access to it and possibly ingesting it. The researcher also recommended a childhood risk prevention and reduction program targeted at under-five children (especially those within the age of 1-...