Background Previous studies on maternal folate status during pregnancy and child asthma risk yielded mixed results, and few considered maternal asthma history, a known risk factor of childhood asthma. This study examined whether the role of maternal folate in childhood asthma differs by maternal asthma history and whether there is an interaction between the two factors. Methods This study included 1948 mother-child dyads from the Boston Birth Cohort. Childhood asthma was defined based on physician diagnosis documented in electronic medical records, and maternal asthma was based on standard questionnaire interview. Maternal plasma folate level within a few days of delivery was measured by chemiluminescent immunoassay. Logistic regression models were applied to examine individual and joint associations of maternal asthma history and plasma folate level with childhood asthma, adjusting for other covariables. Results When stratified by maternal asthma history, an L-shaped relationship between maternal folate level and child asthma was observed in children born to mothers with asthma history (p(interaction) = 0.03). The highest risk was found in children having maternal asthma history and low maternal folate level (odds ratio = 5.93; 95% confidence interval: 2.86-12.3) compared with children without maternal asthma history and with sufficient maternal folate levels. Sensitivity analyses using different definitions of asthma and stratified by major covariables yielded similar findings. Conclusion In this US prospective high-risk birth cohort, maternal asthma history and low folate level interactively increased the risk of child asthma. If further confirmed, optimizing maternal folate levels during pregnancy may mitigate child asthma risk in the setting of maternal asthma history.