We redesigned the undergraduate introductory biology course by writing a new textbook (Integrating Concepts in Biology [ICB]) that follows first principles of learning. Our approach emphasizes primary data interpretation and the utility of mathematics in biology, while de-emphasizing memorization. This redesign divides biology into five big ideas (information, evolution, cells, emergent properties, homeostasis), addressing each at five levels of organization (molecules, cells, organisms, populations, ecological systems). We compared our course outcomes with two sections that used a traditional textbook and were taught by different instructors. On data interpretation assessments administered periodically during the semester, our students performed better than students in the traditional sections (p = 0.046) and exhibited greater improvement over the course of the semester (p = 0.015). On factual content assessments, our students performed similarly to students in the other sections (p = 0.737). Pre- and postsemester assessment of disciplinary perceptions and self-appraisal indicate that our students acquired a more accurate perception of biology as a discipline and may have developed a more realistic evaluation of their scientific abilities than did the control students (p < 0.05). We conclude that ICB improves critical thinking, metacognition, and disciplinary perceptions without compromising content knowledge in introductory biology.