Progress in cryo-electron microscopy has provided the potential for large-size protein structure determination. However, the success rate for solving multi-domain proteins remains low because of the difficulty in modelling inter-domain orientations. Here we developed domain enhanced modeling using cryo-electron microscopy (DEMO-EM), an automatic method to assemble multi-domain structures from cryo-electron microscopy maps through a progressive structural refinement procedure combining rigid-body domain fitting and flexible assembly simulations with deep-neural-network inter-domain distance profiles. The method was tested on a large-scale benchmark set of proteins containing up to 12 continuous and discontinuous domains with medium- to low-resolution density maps, where DEMO-EM produced models with correct inter-domain orientations (template modeling score (TM-score) >0.5) for 97% of cases and outperformed state-of-the-art methods. DEMO-EM was applied to the severe acute respiratory syndrome coronavirus 2 genome and generated models with average TM-score and root-mean-square deviation of 0.97 and 1.3 Å, respectively, with respect to the deposited structures. These results demonstrate an efficient pipeline that enables automated and reliable large-scale multi-domain protein structure modelling from cryo-electron microscopy maps.