Contemporary science educators must equip their students with the knowledge and practical know-how to connect multiple disciplines like mathematics, computing and the natural sciences to gain a richer and deeper understanding of a scientific problem. However, many biology and earth science students are prejudiced against mathematics due to negative emotions like high mathematical anxiety and low mathematical confidence. Here, we present a theoretical framework that investigates linkages between student engagement, mathematical anxiety, mathematical confidence, student achievement and subject mastery. We implement this framework in a large, first-year interdisciplinary science subject and monitor its impact over several years from 2010 to 2015. The implementation of the framework coincided with an easing of anxiety and enhanced confidence, as well as higher student satisfaction, retention and achievement. The framework offers interdisciplinary science educators greater flexibility and confidence in their approach to designing and delivering subjects that rely on mathematical concepts and practices.