Objectives: Anxiety and depression are commonly occurring mental disorders in school-going students and if not considered can result in a worse outcome. The objective of our study was to determine the prevalence, risk factors and relationship of anxiety and depression with different variables among high school students of Karachi. Methods: This cross-sectional study was conducted in October - November 2020 in government and private high schools of four districts of Karachi. Two stage cluster sampling was used to select study sites with 400 students inducted. Data was collected by using Aga Khan University Scale of anxiety and depression. Relationship of outcome with predictor variables was examined by applying univariate and multivariate logistic regression analysis. Results: Overall 53.2% participants reported anxiety and depression out of which 78.8% were females. Participants who were studying in private schools (OR 0.39, CI 0.21-0.69 at 95%, p=0.002) and had mothers who were housewives (OR 0.28, CI 0.09-0.83 at 95%, p=0.022) were less likely to develop anxiety and depression. Participants whose fathers and mothers had a history of anxiety and depression were three times more likely to develop anxiety and depression (OR 3.12, CI 1.52-6.41 at 95%, p=0.002) and (OR 3.02, CI 1.39-6.59 at 95%, p=0.005) respectively. Conclusion: The study found a high prevalence of anxiety and depression among high school students. Female students of public sector school and those who had a family history of anxiety and depression were more likely to develop it. Early detection and management of anxiety and depression by screening are necessary to overcome this burden. doi: https://doi.org/10.12669/pjms.38.4.5093 How to cite this:Ibbad S, Baig LA, Ahmer Z, Shahid F. Prevalence of anxiety and depression in high school students of Karachi, Pakistan. Pak J Med Sci. 2022;38(4):---------. doi: https://doi.org/10.12669/pjms.38.4.5093 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.