This study aimed to determine the effectiveness of Think Pair Share learning based on questions models to increase students’ participation and learning outcomes in studies of the histological structure of the digestive system. To achieve these objectives, research was conducted on the Biology study program at the Faculty of Mathematics and Natural Sciences, Ganesha University of Education. Research sample was the second semester students, amount of 17 students. The design of this study was one short case study. Instruments used in this study included questionnaires and observation sheets to assess students’ participation and responses in learning, and knowledge tests to assess student cognitive learning outcomes. The results obtained by the value of students’ participation were 47.1% in the good category and 47.1% in the very good category with an average value of 83.12. Cognitive learning outcomes obtained a mean value of 76.0. Students who got a greater or equal value of 70.0 were 76.5%. The conclusion of this research were that the Think Pair Share Learning model based on questions could increase students’ participation and learning outcomes in the study of the Histological Structure of the Digestive System.