This study reports the secondary analysis of evaluation data from an innovative high school biology curriculum focused on infectious disease (ID) to examine the health literacy implications of teaching claims evaluation, data interpretation, and risk assessment skills in the context of 21st-Century health science. The curriculum was implemented between 2010 and 2013 in Biology II classes held in four public high schools (three in Massachusetts and one in Ohio), plus a private school in Virginia. A quasi-experimental design was used in which student participants (n = 273) were compared to an age-matched, nonparticipant, peer group (N = 125). Participants in each school setting demonstrated increases in conceptual content knowledge (Cohen's d > 1.89) as well as in understanding how to apply scientific principles to health claims evaluation and risk assessment (Cohen's d > 1.76) and in self-efficacy toward learning about ID (Cohen's d > 2.27). Participants also displayed enhanced communication about ID within their social networks relative to the comparison group (p < 0.05). The data show that integrating the claims evaluation, data interpretation, and risk assessment skills critical for 21st-century health literacy health into high school biology classrooms is effective at fostering both the skills and self-efficacy pertinent to health literacy learning in diverse populations.