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Whether artificial intelligence (AI) analysis of single-lead ECG (1 L ECG) can predict incident AF is unknown. In the VITAL-AF trial (ClinicalTrials.gov NCT03515057, registered 2/24/2021) of primary care patients aged ≥65 years undergoing handheld 1 L ECG screening, we tested three AI approaches to incident AF prediction, and compared the best model to the CHARGE-AF risk score. In a test set of 4,221 individuals, a published AI model trained using single standard ECG leads ("1 L ECG-AI") provided similar 2-year AF discrimination to models trained with VITAL-AF data. In the full VITAL-AF sample of 15,694 individuals without prevalent AF (2-year incident AF 3.1%), 1 L ECG-AI with age/sex (1 L ECG-AI AS) had comparable discrimination (area under the receiver operating characteristic curve [AUROC] 0.695[0.637-0.742]; average precision [AP] 0.060[0.050-0.078]) to CHARGE-AF (AUROC 0.679[0.623-0.730]; AP 0.062[0.052-0.080], AUROC p = 0.46, AP p = 0.92). Net reclassification improvement was favorable versus age ≥65 years (0.27[0.22-0.32]). 1 L ECG-AI may increase efficiency and reach of AF screening.