Background: The study aimed to investigate the association between environmental tobacco smoke exposure and the risk of wheezing among rural and urban preschool children in Mpumalanga province, South Africa, an area associated with poor air quality. Methods: In this study, parents/caregivers of preschool children (n=3145) completed a modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Data were analysed using multiple logistic regression models. Results: The overall prevalence of Wheeze ever was 15.14%, with a higher prevalence in urban pre-schoolers than rural pre-schoolers (20.71% vs 13.30 %, P<0.000). Moreover, the total prevalence of asthma ever was 2.34%. The prevalence was greater in urban pre-schoolers than in rural pre-schoolers (3.92% vs 1.81%, P<0.001). In the final adjusted model, both urban and rural area children who lived with one or more people who smoked in the same household (WE: OR 1.44, 95% CI 1.11-1.86) (CW: OR 2.09, 95% CI 1.38-3.16) and (AE: OR 2.49, 95% CI 1.12-5.54) were found to have an increased likelihood of having Wheeze Ever, Current Wheeze and Asthma Ever as compared to those who lived with non-smokers. Conclusions: The implementation of smoking limits and prohibition is crucial in areas that are frequented or utilized by children. Hence, it is imperative for healthcare providers to actively champion the rights of those who do not smoke within the society, while also endorsing legislative measures aimed at curtailing the extent of tobacco smoke exposure.