Background The export drive for watermelon production is huge and so is pesticide usage. However, the health and safety of the farmers, as well as threat to the environment lie in the shadow. The purpose of the study is to evaluate watermelon farmers’ knowledge and application of pesticides in the Central region of Ghana, to ascertain factors associated with the pesticides application. Methods A field survey of 300 farmers were conducted in six communities through questionnaire. Logistic regression model was used to describe and explain burning sensation as the response variable and the factors that likely affect appropriate pesticide usage. Results The results show that farmers were aware of the environmental and health impacts of pesticides use. However, their knowledge of the risks associated with pesticides is not translated into actual practice to avoid the exposure of pesticides. The farmers experienced various levels of health risks symptoms. Health risks symptoms of headache, burning sensation, fever, watering eyes, chest pains, etc., were reported. The most common symptom is burning sensation. A model capturing biosocial factors influencing predisposition to burning sensation was developed. The model revealed that knowledge to identify pests, knowledge to identify diseases and wearing coverall were the most significant factors farmers experienced to influence burning sensation. Conclusion Significant number of watermelon farmers’ experienced health risks symptoms. In order to minimize the health risk symptoms and environmental consequences, educational training programs must involve the farmers and retailers through strong policy intervention.