Lack of accurate methods for early lymphoma detection limits the ability to cure patients. Patients with Non-Hodgkin lymphomas (NHL) who present with advanced disease have worse outcomes. We developed a DNA methylation-based prediction tool for NHL, based on blood samples collected prospectively from 278 apparently healthy patients who were followed for up to 16 years to monitor for NHL development. A predictive score was developed using machine learning methods in a robust training/validation framework. Our predictive score incorporates CpG DNA methylation at 135 genomic positions, with higher scores predicting higher risk. It was 85% and 78% accurate for identifying patients at risk of developing future NHL, in patients with high or low epigenetic mitotic clock respectively, in a validation cohort. It was also sensitive at detecting active NHL (96.3% accuracy) and healthy status (95.6% accuracy) in additional independent cohorts. Scores optimized for specific NHL subtypes showed significant but lower accuracy for predicting other subtypes. Our score incorporates hyper-methylation of Polycomb and HOX genes, which have roles in NHL development, as well as PAX5 - a master transcriptional regulator of B-cell fate. Subjects with higher risk scores showed higher regulatory T-cells, memory B-cells, but lower naïve T helper lymphocytes fractions in the blood. A score based on DNA methylation in blood is accurate at predicting NHL development with lead time of up to 16 years. Future prospective studies will be required to confirm the utility of our signature for managing patients who are at high risk for developing future NHL.