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This study sought to determine the extent to which large class sizes influenced the manner in which teaching and learning were mediated in senior high schools. To achieve this, the survey design was employed. 192 students were purposively selected from four (4) senior high schools in the Asutifi North and South Districts. A questionnaire with a reliability coefficient of 0.791 was used to obtain data from the respondents. Quantitative data analysis was performed using Statistical Products and Service Solutions (SPSS). Both descriptive and inferential statistical tools were used in order to analyze the data, and also answer the research questions. To find out the influence of class size on the teaching and learning of mathematics in SHS, the mean, standard deviation, multiple linear regression as well as Pearson’s product-moment correlation were used to perform the analyses of the data collected. The study revealed that large class sizes influenced students’ academic performance and also limits their learning opportunities of students. It was again unraveled that classroom interactions had a great influence on the student’s academic performance. It has been recommended that small class sizes and good classroom interactions enhance performance. Therefore, teachers and head teachers should make sure they conform to the required teacher-to-student ratio of 1:40 by the Ghana Education Service. Teachers should create an enabling environment for students to participate in classroom activities. Furthermore, the study showed that students performed well in smaller class sizes and good classroom interaction. Therefore, the Government should employ more teachers and build more classrooms to solve the problem of large class sizes in the senior high schools in Ghana.