This study evaluated the effectiveness of the Mathematics Infusion into Science Project (MiSP), which integrated science and mathematics in an engaging middle school science curriculum that fostered improvements in science content knowledge, higher-level problem solving, and affective domains related to mathematics. The project design was based upon a framework that suggests cross-curricular designs promote scientific thinking and positive attitudes towards the role of mathematics in learning and communicating science. The curriculum incorporated graphing skills that complemented eighth grade science concepts such as thermal energy transfer, density, and photosynthesis. Using a quasi-experimental wait-list control design, this research explored the impacts of MiSP in terms of students’ content knowledge, application ability, reasoning skills, and affective domains over the course of one academic year. Over two academic years, 28 teachers participated in 87 h of professional development and 1135 students experienced mathematics-infused lessons and completed pre- and post-science assessments and attitude surveys. Data analyses utilizing analysis of covariance indicated significant improvements in science disciplinary knowledge, higher-order science process skills, and select affective domains, with small to medium effects. Further analyses indicated that treatment-related improvement in science process skills was not mediated by the significant affective domains including linear equation confidence, graph construction confidence, and mathematics applicability recognition. Quantitative findings support the use of graphing-infused curricula in middle schools to improve student science learning and mathematics-related attitudes. Implications for implementing science-mathematics integrated curricula and assessing reform-based science initiatives are discussed.