Owing to their layered structure and higher theoretical specific capacity, MoS2-based materials have evoked tremendous attention for sodium storage. However, their sluggish ionic transport dynamics and unavoidable volume variation always lead to an unsatisfactory electrochemical performance, thereby hindering their further development. Herein, the Se-doped MoS2 nanosheets confined in hollow mesoporous carbon nanospheres (MoSSe@C) were successfully prepared via a synergistic strategy combining defect design and structure optimization. Thereinto, the larger Se atom doping could regulate the crystal structure and provide abundant defects, leading to increased conductivity, fast diffusion kinetics, and abundant active sites. Besides, it also could effectively expand the interlamellar spacing of the internal MoS2 nanosheets, thereby releasing more intrafacial active sites for sodium storage. The external hollow mesoporous carbon nanospheres effectively adapt the volume fluctuation of the MoSSe@C electrode during the repeated cycling. Furthermore, the interior anion defects induced by Se doping and exterior HMCs synergistically boost the conductivity and fasten the redox kinetics of the MoSSe@C electrode. As a result, the electronic structure is tailored both internally and externally, thereby contributing greatly to the rapid reaction dynamics. Thus, the MoSSe@C electrode exhibits a favorable performance (450/150 mAh g–1 at 0.1 A g–1) in half/full cells, respectively.