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Abstract Background Anemia among adolescents (ages 10–19 years) is a leading cause of morbidity and mortality in low- and middle-income countries and carries long-term health and economic consequences. To address the issue, policymakers and programmers require evidence of the burden of anemia among adolescents in specific contexts, as well as an understanding of the factors associated with anemia in this population. Methods We conducted a cross-sectional survey as a baseline assessment to determine the prevalence and factors associated with anemia in secondary school students, as part of a cluster-randomized effectiveness trial testing different micronutrient supplementation strategies in addressing anemia among adolescents in Zanzibar. Between March 7th to 25th, 2022 the survey was conducted on 2,479 school-going adolescents aged 10–17 years from 42 schools on the island of Zanzibar, Tanzania. Hemoglobin concentration was measured along with the collection of socio-demographics, health, food frequency, and water, sanitation and hygiene data. Results Based on the World Health Organization cutoffs for anemia, 53.3% of the sample had anemia (mild, moderate, or severe). Using chi-square tests and logistic regressions, we determined that females had higher odds of anemia than males (Adjusted OR = 1.47; 95% CI: 1.24, 1.74), those in the highest wealth quintile had lower odds of anemia than those in the lowest wealth quintile (Adjusted OR = 0.7; CI: 0.54, 0.91), stunted adolescents had higher odds of anemia than non-stunted students (Adjusted OR = 1.38; 95% CI: 1.06,1.81), and those who used shared toilets had higher odds of moderate or severe anemia than those with private toilet access (Adjusted OR = 1.68; CI: 1.07, 2.64). Conclusions The high prevalence of anemia in this sample indicates an urgent need to address anemia among adolescents in Zanzibar, and the factors associated with anemia point to the importance of water, sanitation, and hygiene interventions in addition to dietary and nutritional support. Trial Registration NCT05104554, registered 03/11/2021.