Uganda has persistently had high adolescent pregnancy prevalence; 25% for the last 10 years. This protocol presents the design of a Cluster Randomized Controlled Trial (CRCT) to investigate the effectiveness of School-Based Sexual and Reproductive Health (SBSRH) interventions on prevention of pregnancy among school girls aged 15–19 years in the Hoima District, Uganda. 18 secondary schools (clusters) will be selected using cluster sampling and allocated 1:1 into control or intervention group stratified by geographical location. 1080 (60 each cluster) participants/girls aged 15–19 years will be selected using simple random sampling. The intervention group will receive tailored SRH information, in-school medical care and referral over 12 months. The control group will receive no intervention from the research team; however, they can access alternative services elsewhere if they wish. Data will be obtained at baseline, 6 months and 12 months. The outcomes are reduction in occurrence of pregnancy, utilization of SRH services and sexual behavioral change. To our knowledge, this is the first CRCT providing combined SRH interventions for prevention of adolescent pregnancy in Uganda. If effective, it could have great potential in preventing adolescent pregnancy. Trial Registration: Pan African Clinical Trial Registry (PACTR201810882140200) Registered on 16 October 2018.