This study describes the implementation and effectiveness of small-group active engagement (GAE) exercises in an introductory biology course (BSCI207) taught in a large auditorium setting. BSCI207 (Principles of Biology III—Organismal Biology) is the third introductory core course for Biological Sciences majors. In fall 2014, the instructors redesigned one section to include GAE activities to supplement lecture content. One section (n = 198) employed three lectures per week. The other section (n = 136) replaced one lecture per week with a GAE class. We explored the benefits and challenges associated with implementing GAE exercises and their relative effectiveness for unique student groups (e.g., minority students, high- and low-grade point average [GPA] students). Our findings show that undergraduates in the GAE class exhibited greater improvement in learning outcomes than undergraduates in the traditional class. Findings also indicate that high-achieving students experienced the greatest benefit from GAE activities. Some at-risk student groups (e.g., two-year transfer students) showed comparably low learning gains in the course, despite the additional support that may have been afforded by active learning. Collectively, these findings provide valuable feedback that may assist other instructors who wish to revise their courses and recommendations for institutions regarding prerequisite coursework approval policies.