Opportunities for large numbers of undergraduates to engage in authentic research experiences are limited in many large public institutions. These large public institutions serve the vast majority of students who are historically underrepresented in STEM fields, such as first-generation, low-income students of color. Although a course-based undergraduate research experience (CURE) is one scalable approach to providing such opportunities, there is limited evidence about the impact of participation, particularly for students historically underrepresented in science. This study provides evidence of the influence of student participation in a CURE on undergraduate science course grades using an experimental design and multiple years of data from students at a Hispanic-serving institution. Course grades were compared for five different science courses across five cohorts of students participating in a CURE (n = 935) and a similar group of students who did not participate in the CURE (n = 1,144). CURE students had significantly higher overall grades in a lecture course directly related to the CURE even after statistically adjusting for demographic and academic characteristics. Implications for CUREs as a model for improving science knowledge and achievement for students typically underrepresented in STEM fields are discussed.