Due to their hydrophilic, biocompatible and adjustability properties, hydrogels have received a lot of attention. The introduction of nucleic acids has made hydrogels highly stimuli-responsiveness and they have become a new generation of intelligent biomaterials. In this review, the development and utilization of smart nucleic acid hydrogels (NAHs) with a high stimulation responsiveness were elaborated systematically. We discussed NAHs with a high stimuli-responsiveness, including pure NAHs and hybrid NAHs. In particular, four stimulation factors of NAHs were described in details, including pH, ions, small molecular substances, and temperature. The research progress of nucleic acid hydrogels in biomedical applications in recent years is comprehensively discussed. Finally, the opportunities and challenges facing the future development of nucleic acid hydrogels are also discussed.