In the USA, Organic Chemistry I is a gateway course for undergraduate students seeking careers in medical- and health-related fields. Estimates of failure and withdrawal rates are approximately 40% at some large, public institutions and higher for specific segments of the student population, such as ethnic minorities, those of low socio-economic status, and non-traditional students. We applied a multi-layered contextual model of student success to investigate various factors contributing to the academic success of undergraduate students in Organic Chemistry I. Participants were 20 undergraduate students formerly enrolled in Organic Chemistry I at an urban, 4-year public institution located in the northeastern USA. Using semi-structured interviews, we examined students’ divergent academic outcomes, as well as internal, proximal, and distal variables relating to positive academic outcomes. Results suggest that at-risk students’ success in Organic Chemistry I is facilitated by support from qualified mentors, availability and utilization of academic resources, and proficiency in science. We discuss these results within a contextual framework and offer practical suggestions for educators.