Background: While a parental history of asthma has been widely reported as a risk factor for childhood asthma, less is known about the impact of multigenerational family history of asthma on the occurrence of asthma in children. Methods: From 2012 to 2013, a cross-sectional study was carried out in seven Chinese cities. Participants were randomly selected from 94 middle schools, elementary schools and kindergartens. Questionnaires, from which information on asthma, environmental exposure and family members (parents, paternal grandparents and maternal grandparents) affected by asthma were obtained, were completed by the children’s parents or guardians. Two-level logistic regressions were used to assess hereditary patterns of asthma, adjusted for potential confounding factors. Mediation analysis was performed to estimate the potential mediation effect of parents on the association between grandparental asthma and offspring asthma. Results: A paternal grandfather (OR: 2.59, 95%CI: 2.14-3.13), paternal grandmother (OR: 2.40, 95%CI: 1.93-2.99), maternal grandfather (OR: 2.08, 95%CI: 1.71-2.53) and maternal grandmother (OR: 2.08, 95%CI: 1.67-2.59) with asthma were associated with childhood asthma, independent of parental asthma. Of the children who had two family members with asthma, the risk of childhood asthma was highest when both parents had asthma (OR: 15.92, 95%CI: 4.66-54.45) or when both father and paternal grandfather had asthma (OR: 11.11, 95%CI: 5.77-21.38). Parents had a small proportion of mediation effect on the association between grandparental asthma and childhood asthma. Conclusions: A family history of grandparental asthma was associated with childhood asthma and parents only partially mediate the association.