Summary Objective We evaluated whether deep learning applied to whole‐brain presurgical structural connectomes could be used to predict postoperative seizure outcome more accurately than inference from clinical variables in patients with mesial temporal lobe epilepsy (TLE). Methods Fifty patients with unilateral TLE were classified either as having persistent disabling seizures (SZ) or becoming seizure‐free (SZF) at least 1 year after epilepsy surgery. Their presurgical structural connectomes were reconstructed from whole‐brain diffusion tensor imaging. A deep network was trained based on connectome data to classify seizure outcome using 5‐fold cross‐validation. Results Classification accuracy of our trained neural network showed positive predictive value (PPV; seizure freedom) of 88 ± 7% and mean negative predictive value (NPV; seizure refractoriness) of 79 ± 8%. Conversely, a classification model based on clinical variables alone yielded <50% accuracy. The specific features that contributed to high accuracy classification of the neural network were located not only in the ipsilateral temporal and extratemporal regions, but also in the contralateral hemisphere. Significance Deep learning demonstrated to be a powerful statistical approach capable of isolating abnormal individualized patterns from complex datasets to provide a highly accurate prediction of seizure outcomes after surgery. Features involved in this predictive model were both ipsilateral and contralateral to the clinical foci and spanned across limbic and extralimbic networks.