Nanofiber-based hydrogels (NFHGs) prepared by the combination of traditional hydrogels and novel nanofibers have demonstrated great potential in various application fields, owing to their integrated advantages of superhydrophilicity, high water-holding capacity, good biocompatibility, enhanced mechanical strength, and excellent structural tenability. In this review, a comprehensive overview of the structure design and synthetic strategy of NFHGs derived from electrospinning technique, weaving, freeze-drying, 3D printing, and molecular self-assembling method is provided. The widely researched multifunctional applications, primarily involving tissue engineering, drug delivery, sensing, intelligent actuator, and oil/water separation are also presented. Furthermore, some unsolved scientific issues and possible directions for future development of this field are also intensively discussed.