Abstract Background Cataract diagnosis typically requires in-person evaluation by an ophthalmologist. However, color fundus photography (CFP) is widely performed outside ophthalmology clinics, which could be exploited to increase the accessibility of cataract screening by automated detection. Methods DeepOpacityNet was developed to detect cataracts from CFP and highlight the most relevant CFP features associated with cataracts. We used 17,514 CFPs from 2573 AREDS2 participants curated from the Age-Related Eye Diseases Study 2 (AREDS2) dataset, of which 8681 CFPs were labeled with cataracts. The ground truth labels were transferred from slit-lamp examination of nuclear cataracts and reading center grading of anterior segment photographs for cortical and posterior subcapsular cataracts. DeepOpacityNet was internally validated on an independent test set (20%), compared to three ophthalmologists on a subset of the test set (100 CFPs), externally validated on three datasets obtained from the Singapore Epidemiology of Eye Diseases study (SEED), and visualized to highlight important features. Results Internally, DeepOpacityNet achieved a superior accuracy of 0.66 (95% confidence interval (CI): 0.64–0.68) and an area under the curve (AUC) of 0.72 (95% CI: 0.70–0.74), compared to that of other state-of-the-art methods. DeepOpacityNet achieved an accuracy of 0.75, compared to an accuracy of 0.67 for the ophthalmologist with the highest performance. Externally, DeepOpacityNet achieved AUC scores of 0.86, 0.88, and 0.89 on SEED datasets, demonstrating the generalizability of our proposed method. Visualizations show that the visibility of blood vessels could be characteristic of cataract absence while blurred regions could be characteristic of cataract presence. Conclusions DeepOpacityNet could detect cataracts from CFPs in AREDS2 with performance superior to that of ophthalmologists and generate interpretable results. The code and models are available at https://github.com/ncbi/DeepOpacityNet (https://doi.org/10.5281/zenodo.10127002).