This study examined the effect of e-learning on the academic performance of learners at St. Mary's Simbya Secondary School in Bundibugyo District, Uganda. The study was informed by the increasing integration of digital technologies in education and the need to understand how such technologies affected learning outcomes in resource-constrained rural settings. Three specific objectives guided the study: to assess the extent of e-learning adoption at St. Mary's Simbya Secondary School, to determine the effect of e-learning tools and platforms on learners' academic performance, and to identify the factors that mediated or moderated the relationship between e-learning and academic performance. A mixed-methods research design was employed, combining a quasi-experimental comparison of examination scores between e-learning users and non-users with a questionnaire survey and qualitative interviews. The study involved 150 students and 20 teachers. Analysis of Uganda Certificate of Education (UCE) preliminary scores showed that students who regularly used e-learning resources achieved a mean score of 64.8% compared to 52.3% for non-users, a statistically significant difference (t = 6.24, p < 0.001). Regression analysis indicated that frequency of e-learning use (β = 0.442), teacher digital literacy (β = 0.319), and availability of digital devices (β = 0.287) were significant positive predictors of academic performance (R² = 0.624). Key barriers to e-learning effectiveness included unreliable electricity supply, limited device availability, inadequate teacher training, and poor internet connectivity. The study concluded that e-learning had a significant positive effect on academic performance when supported by adequate infrastructure and teacher capacity, and recommended targeted investments in digital infrastructure, teacher training, and device provision to maximize the academic benefits of e-learning in secondary schools in Bundibugyo.