The study investigated the relationship between school size and student academic performance in secondary schools in Makindye Division, Kampala, Uganda. A cross-sectional survey design grounded in a mixed-methods framework was adopted, with data collected from a total sample of 172 respondents comprising 130 students, 32 teachers, and 10 school administrators drawn from eight purposively selected secondary schools. Structured questionnaires, semistructured interview guides, and document analysis were used as instruments for data collection. Quantitative data were analyzed using Pearson's correlation coefficient, descriptive statistics, and regression analysis, while qualitative data were subjected to thematic analysis. Findings revealed a statistically significant negative relationship between school size and student academic performance (r = -0.61, p < 0.05), indicating that as enrolment size increased beyond manageable thresholds, student academic outcomes tended to decline. Large schools were associated with high student-to-teacher ratios, inadequate learning resources, overcrowded classrooms, reduced teacher-student interaction, and diminished institutional attention to individual learners. The study concluded that school size was a meaningful structural determinant of academic outcomes in secondary schools and recommended that education authorities in Makindye Division and Uganda more broadly establish and enforce optimal school enrolment ceilings to protect the quality of teaching and learning.