Precise preoperative evaluation of drug-resistant epilepsy (DRE) requires accurate analysis of invasive stereoelectroencephalography (SEEG). With the tremendous breakthrough of Artificial intelligence (AI), previous studies can help clinical experts to identify pathological activities automatically. However, they still face limitations when applied in real-world clinical DRE scenarios, such as sample imbalance, cross-subject domain shift, and poor interpretability. Our objective is to propose a model that can address the above problems and realizes high-sensitivity SEEG pathological activity detection based on two real clinical datasets.Our proposed innovative and effective SEEG-Net introduces a multiscale convolutional neural network (MSCNN) to increase the receptive field of the model, and to learn SEEG multiple frequency domain features, local and global features. Moreover, we designed a novel focal domain generalization loss (FDG-loss) function to enhance the target sample weight and to learn domain consistency features. Furthermore, to enhance the interpretability and flexibility of SEEG-Net, we explain SEEG-Net from multiple perspectives, such as significantly different features, interpretable models, and model learning process interpretation by Grad-CAM++.The performance of our proposed method is verified on a public benchmark multicenter SEEG dataset and a private clinical SEEG dataset for a robust comparison. The experimental results demonstrate that the SEEG-Net model achieves the highest sensitivity and is state-of-the-art on cross-subject (for different patients) evaluation, and well deal with the known problems. Besides, we provide an SEEG processing and database construction flow, by maintaining consistency with the real-world clinical scenarios.According to the results, SEEG-Net is constructed to increase the sensitivity of SEEG pathological activity detection. Simultaneously, we settled certain problems about AI assistance in clinical DRE, built a bridge between AI algorithm application and clinical practice.Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.