Over the past decades, enormous efforts have been made to improve the performance of linear or nonlinear mixing models for hyperspectral unmixing (HU), yet their ability to simultaneously generalize various spectral variabilities (SVs) and extract physically meaningful endmembers still remains limited due to the poor ability in data fitting and reconstruction and the sensitivity to various SVs. Inspired by the powerful learning ability of deep learning (DL), we attempt to develop a general DL approach for HU, by fully considering the properties of endmembers extracted from the hyperspectral imagery, called endmember-guided unmixing network (EGU-Net). Beyond the alone autoencoder-like architecture, EGU-Net is a two-stream Siamese deep network, which learns an additional network from the pure or nearly pure endmembers to correct the weights of another unmixing network by sharing network parameters and adding spectrally meaningful constraints (e.g., nonnegativity and sum-to-one) toward a more accurate and interpretable unmixing solution. Furthermore, the resulting general framework is not only limited to pixelwise spectral unmixing but also applicable to spatial information modeling with convolutional operators for spatial–spectral unmixing. Experimental results conducted on three different datasets with the ground truth of abundance maps corresponding to each material demonstrate the effectiveness and superiority of the EGU-Net over state-of-the-art unmixing algorithms. The codes will be available from the website: https://github.com/danfenghong/IEEE_TNNLS_EGU-Net .