Objective: To explore the interaction of health literacy and second-hand smoke exposure on psychopathological symptoms of middle school students. Methods: From November 2015 to January 2016, 22 628 middle school students from Shenyang of Liaoning Province, Bengbu of Anhui Province, Xinxiang of Henan Province, Ulanqab of Inner Mongolia Autonomous Region, Chongqing Municipality, and Yangjiang of Guangdong Province were enrolled by using the multi-stage cluster convenience sampling method. A questionnaire was used to collect the data including demographic information, health literacy, second-hand smoke exposure, and psychopathological symptoms. A multivariate logistic regression model was used to analyze the interaction of health literacy and second-hand smoke exposure on psychopathological symptoms of middle school students. Results: The age of students was (15.36±1.79) years old, of which 10 990 were boys, accounting for 48.6% of total students. The detection rate of psychopathological symptoms was 29.1% (6 581/22 628). The detection rate of psychopathological symptoms in those who were exposed to second-hand smoke was 38.1% (2 401/6 304), which was higher than that in the non-second-hand smoke exposure group [25.6% (4 180/16 324)] (P<OR (95%CI) of the interaction between medium and low levels of overall health literacy, low level of interpersonal dimension of health literacy and second-hand smoke exposure was 1.19 (1.15-1.24), 2.00 (1.92-2.10) and 1.59 (1.52-1.66), respectively. Conclusion: There was a positive interaction between middle and low levels of overall health literacy, low level of interpersonal dimension of health literacy and second-hand smoke exposure on psychopathological symptoms of middle school students.