This study aimed to investigate health literacy and its association with liver fluke prevention and control among students in risk areas. A cross-sectional descriptive study was conducted among 20 schools from 20 provinces in northeast Thailand, between May to June 2017. Students were selected by cluster random sampling and they completed constructive questionnaires. The association between health literacy and liver fluke prevention and control was analyzed by using multiple logistic regressions. A total of 1,100 students was included in the study. The majority were females (75.82%). The majority of the students (84.09%)need to modify their practice level regarding liver fluke prevention and control. Health literacy at the highest level was significantly associated with good practice, and included cognitive skills (ORadj = 2.11, 95%CI: 1.15-3.86, p = 0.026), communication skills (ORadj = 2.63, 95%CI: 1.58-4.40, p<0.001), and media literacy skills (ORadj = 1.78; 95%CI: 1.12-2.83; p-value = 0.030). In conclusion, health literacy can be used as a desirable strategy for informing those with a lower practice level regarding liver fluke prevention and control among secondary school students in Northeastern Thailand. This study indicates that behavior intervention is urgently needed, especially cognitive skills, communication skills, and media literacy skills.