Kentucky experiences the highest overall cancer incidence and mortality rates in the USA with the greatest burden in the eastern, Appalachian region of the state. Cancer disparities in Kentucky are driven in part by poor health behaviors, poverty, lack of health care access, low education levels, and low health literacy. Individuals with inadequate health literacy are less likely to participate in preventive measures such as obtaining screenings and making healthy lifestyle choices, thus increasing their chances of developing and dying from cancer. By increasing cancer literacy among youth and adults, it may be possible to decrease cancer disparities across Kentucky. This study aimed to establish connections with middle and high schools in Kentucky that would facilitate pilot implementation of a brief cancer education intervention and assessment of cancer health literacy among these student populations. A baseline pretest cancer literacy survey consisting of 10 items was given to 349 participants, followed by the delivery of a cancer education presentation. Immediately following the presentation, participants were given a posttest with identical items to the pretest. Participants were primarily Caucasian (89.4%), female (68.7%), and in 10th through 12th grade (80.5%). Significant (p < 0.0001) increases in both average and median percent of correctly marked items were observed between the pretest and posttest (average, pretest = 56% versus posttest = 85%; median, pretest = 60% versus posttest = 90%). The scores for all individual items increased after the brief intervention. The results demonstrated a significant increase in cancer literacy levels immediately after the pilot educational intervention. We suggest that it may be possible to improve cancer literacy rates in Kentucky by integrating cancer education into middle and high school science and/or health education curricula. This could ultimately drive changes in behaviors that may help lower cancer incidence and mortality rates. Plans for future interventional studies measuring long-term cancer knowledge retention and resultant behavioral changes among middle and high school students as well as the feasibility of integrating cancer education into middle and high school curricula are also discussed.