This study explored high school science teachers’ curriculum, instructional and assessment decisions for inclusive science classrooms. We also attempted to determine the factors that influence their decisions. The sample comprised thirteen science teachers from two high schools in the Midwest of the USA. One of the schools had failed to meet the Academic yearly progress under the federal No Child Left Behind (NCLB) Act in the four years prior to this study because of its Student with Disabilities (SWD) sub-group. Data were collected through a questionnaire and semi-structured interviews. Results show that science teachers’ curriculum, instructional and assessment decisions were influenced by factors associated with accountability and personal interests and preferences of science teaching methods. Although science teachers’ decisions were within the framework that integrates content and practical classroom knowledge for regular classes, such decisions may not promote effective science teaching and learning in inclusive classes. As such, most science teachers exhibited lack of knowledge about effective science teaching in inclusive classrooms. These findings have implications on science teacher education and science teaching in inclusive classrooms.