Online engagement, or the use of online supplementary instruction and assessment, in high-structure courses is gaining popularity as a useful tool to facilitate instruction, assignments, and examinations. High-structure courses, which include regular pre- and post-class assessments and significant active learning during class, have been shown to increase student engagement and improve student performance, whereas electronic learning has shown mixed results. The goal of this study was to assess online engagement in a large-enrollment, lecture-style undergraduate cell biology course. The course was taught using a high-structure approach that required students to read the textbook and complete assignments before class, actively participate in class, complete review quizzes after class, and assess learning through examinations. Use of the online component was voluntary and included the e-book, associated online guides, videos, hyperlinks, experimental walk-throughs, and enhanced practice questions not found in the textbook. We found that while a statistically significant difference on preclass assignments resulted from voluntary use of the online component, no difference was observed on examinations. Satisfaction or future-use scores did not stratify along preclass assignments or examinations. Future studies are needed to define how to successfully incorporate online engagement in high-structure large lecture courses.