Background: Many studies document associations between low health literacy (HL) and poor health behaviors and outcomes. Yet, HL is understudied among adolescents, particularly from underserved, rural communities. We targeted rural adolescents in this cross-sectional study and explored relationships between HL and (1) energy-balance-related health behaviors and (2) body mass index (BMI) and quality of life (QOL). Methods: Surveys were administered to 7th graders across 8 middle schools in rural Appalachia. HL was assessed using the Newest Vital Sign. Energy-balance-related behaviors and QOL were assessed using validated instruments. Height and weight were objectively measured. Analyses were conducted using the Hodges-Lehmann nonparametric median difference test. Results: Of the 854 adolescent students (mean age = 12; 55% female), 47% had limited HL. Relative to students with higher HL, students with lower HL reported significantly lower frequency of health-promoting behaviors (water, fruit and vegetable intake, physical activity, sleep), higher frequency of risky health behaviors (sugar-sweetened beverages, junk food, screen time), and had higher BMI percentiles and lower QOL (all p < 0.05). Conclusions: Low HL is associated with energy-balance-related behaviors, BMI, and QOL among rural, Appalachian adolescents. Findings underscore the relevance of HL among rural middle school students and highlight implications for school health.