This cross-sectional, observational study examined how school-level academic performance and enrollment in the physical sciences (Earth science, chemistry, and physics) mediate the predictive value of socioeconomic status on graduation rate in U.S. high schools. Data were collected from N = 555 schools (475,539 students) that reported enrollment and passing rates on physical science standardized assessments. A structural equation model accounted for the hierarchical nature of the physical sciences and controlled for the influence of school size. Results indicated that chemistry enrollment and Earth science performance partially mediated the effects of poverty on graduation rates. These results provide high need schools with a roadmap for increasing graduation rates through targeted interventions in physical science participation and performance, which may facilitate pathways to postsecondary STEM study and careers.