Infectious diseases ranging from the common cold to cholera affect our society physically, emotionally, ecologically, and economically. Yet despite their importance and impact, there remains a lack of effective teaching materials for epidemiology and disease ecology in K-12, undergraduate, and graduate curricula [2]. To address this deficit, we’ve developed a classroom lesson with three instructional goals: (1) Familiarize students on basic concepts of infectious disease ecology; (2) Introduce students to a classic compartmental model and its applications in epidemiology; (3) Demonstrate the application and importance of mathematical modeling as a tool in biology. The instructional strategy uses a game-based mathematical manipulative designed to engage students in the concepts of infectious disease spread. It has the potential to be modified for target audiences ranging from Kindergarten to professional schools in science, public health, policy, medical, and veterinarian programs. In addition, we’ve provided variations of the activity to enhance the transfer of fundamental concepts covered in the initial lesson to more complex concepts associated with vaccination and waning immunity. While 10 variations are presented here, the true number of directions in which the game might extend will only be limited by the imagination of its students [6].