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Sexual and reproductive health of youths constitutes a significant public health challenge because of the high risk for morbidity and mortality. There is low uptake of modern contraceptives among the sexually active youths despite availability. We investigated the factors associated with the uptake of modern contraceptives among youths attending secondary schools in Mbale City. This was a cross-sectional study that enrolled 2,690 students from six purposively selected high-volume secondary schools in Mbale City. Data were collected using a validated semi-structured questionnaire and analyzed using descriptive statistics and multivariable logistic regression to identify factors associated with modern contraceptive use. The factors associated with modern contraceptive were stratified by sex. Statistical significance was set at 5% confidence level. Out of 2690 participants, 38.0% were sexually active. The proportion of sexually active participants who had ever used modern contraceptives was 60.9%. Factors associated with modern contraceptive use among male participants were not knowing the fertility days of the female (AOR = 0.49; 95% CI: 0.32-0.77; p = 0.002) and not receiving health education from a health worker (AOR = 0.44; 95% CI: 0.30-0.64; p