Background: In rural communities, understanding and improving school climate may benefit youth facing unique contextual challenges to well-being. As education research rarely focuses on rural schools, we aimed to examine school climate and student well-being with a particular focus on rural schools, compared to suburban schools. Methods: Cross-sectional survey data were collected from 62,265 students in 22 rural and 78 suburban Maryland middle and high schools. Student self-report data were collected on school climate (safety, engagement, and environment) as well as internalizing problems, behavior problems, stress, substance abuse, and future orientation. Multiple-group, multilevel models were fit to compare between rural and suburban schools. Results: On average, rural students reported significantly lower perceptions of safety and engagement than suburban students. Safety and engagement were generally associated with higher youth well-being. A number of moderated effects were observed, which generally suggested stronger associations between school-level climate--particularly engagement--and more positive outcomes for rural compared to suburban students. Conclusions: Students' perceptions of safety and engagement were associated with student well-being, in some cases with stronger associations for rural students. These findings suggest that efforts to improve school climate may be particularly impactful for rural students.