Epidemiological studies have revealed several associations between asthma symptoms and environmental and dietary factors, but the potential environment- diet interactions on asthma incidence have rarely been investigated. The aim of this work was to evaluate the interrelationships between urban/rural environment, adherence to a healthy dietary pattern, the Mediterranean diet, and childhood asthma. A cross-sectional survey was performed and 1125 (529 boys), 10- to 12-year-old children were selected from 18 schools located in urban Athens area (n = 700) and from 10 schools located in rural areas of Ilia and Viotia (n = 425), Greece. Children and their parents completed standardized questionnaires, which evaluated, among others, environmental factors and dietary habits. Asthma was defined according to Phase II of the International Study on Allergies and Asthma in Childhood criteria. Adherence to the Mediterranean diet was assessed using the Mediterranean and Diet Quality Index for children and adolescents (KIDMED) score. Living in urban areas was associated with higher odds of ever had asthma symptoms by 1.78 times (95% confidence interval [CI], 1.25-2.54) when compared with rural areas. In contrast, 1-unit increase in the KIDMED score was associated with 16% lower likelihood of having asthma symptoms (95% CI, 0.77-0.91), after adjusting for various confounders. When stratifying the analysis by area of living it was observed that adherence to the Mediterranean diet was associated with lower likelihood of asthma in both urban and rural areas (urban, odds ratio [OR] = 0.81, 95% CI, 0.73-0.91; rural, OR = 0.87, 95% CI, 0.75-1.00). Urban environment seems to increase the likelihood of childhood asthma, whereas adherence to the healthy Mediterranean dietary pattern could mediate the aforementioned association and confers significant protection.