Background <p>Health behaviors and lifestyles among adolescents are critical public health issues, as they affect both current and future wellbeing, particularly in young-populated developing countries like Ethiopia. Therefore, this study examines key health-related behaviors and lifestyles among adolescents, how these vary by sociodemographic factors, and whether health literacy influences these behaviors and lifestyles while controlling for potential covariates, with the aim of supporting evidence-based interventions.</p> Methods <p>The study was cross-sectional and conducted among adolescents in secondary schools from January 8 to February 27, 2024, in Ethiopia. Participants were recruited using stratified sampling, followed by simple random sampling, and data were collected using a paper-based self-administered questionnaire. Descriptive analyses, chi-square tests, and logistic regression analyses were performed to summarize participants’ sociodemographic data, health behaviors and lifestyles, and health literacy status; to examine variations in these health behaviors and lifestyles; and to assess whether health literacy predicts them after adjusting for potential covariates, respectively, using SPSS version 27.0.</p> Results <p>Seven hundred twenty-two adolescents participated in this study. Key health-related behaviors assessed were: screen time, sleep duration, sexual and reproductive health-related behavior, physical activity, khat chewing, alcohol consumption, smoking, and other substance use. Most participants reported unhealthy behavior in at least one of these issues. Consequently, only about one-fifth of the participants had an overall healthy lifestyle. Unhealthy behaviors co-occur especially in 8.0 to 25.9% of the participants. Unhealthy behaviors and lifestyles were statistically significantly associated with factors such as attending public schools, being in grade 11–12, having parents with low education, a low household income, and inadequate health literacy. Participants having adequate health literacy were more likely to avoid risky sexual behaviors (AOR = 7.227; 95% CI: 3.183, 16.405), chewing khat (AOR = 3.992; 95% CI: 1.393, 11.438), alcohol consumption (AOR = 6.492; 95% CI: 1.469, 28.687), and to have an overall healthy lifestyle (AOR = 2.610; CI: 1.636, 4.165).</p> Conclusion <p>About four-fifths of the adolescents surveyed had an overall unhealthy lifestyle. Some exhibited a high clustering of risky behaviors. Health behaviors and lifestyles among these adolescents varied based on sociodemographic characteristics and health literacy status. This study highlights the need for multi-level, targeted interventions, including health education programs that integrate health literacy and behavioral components, initiatives that equip parents and teachers with necessary knowledge, skills, and resources, and supportive policy frameworks to promote healthy behaviors and lifestyles among adolescents.</p>