This study focuses on the role of culture in student learning. In a comparative study different pedagogical approaches were analyzed using quantitative and qualitative methods in a creatively conceived research design. The key innovation of this study involved course design in the intervention class that used a culturally responsive framework inspired by Indigenous Knowledge Systems. The findings show science learning gains for all students in the course taught with increased cultural relevancy. Underrepresented minority students (URM) were nearly eight times more likely to earn an ‘A’ as a final course grade as compared to URM students in the control course. Female URM students achieved final course grades nearly 10 percentage points or one letter grade higher than female URM students in the control course. Based on the evidence found in this study, culture plays a critical role in learning STEM in undergraduate science courses, particularly those for nonscience majors.