Articular cartilage defect repair is challenging for clinics because it is avascular tissue lack of self-regenerative ability. Gelatin-based hydrogels are widely used in the field of tissue engineering because of their good biodegradability, excellent biocompatibility, and cell/tissue affinity. However, gelatin-based hydrogels exhibit poor thermal stability and low mechanical strength, which limits their applications in cartilage repair. In this study, methacrylic anhydride (MA) was employed to modify gelatin to obtain photo-crosslinkable methacrylated gelatin (GelMA). The GelMA-based natural-synthetic polymer biohybrid hydrogel was prepared by co-polymerizing acrylamide (AM) and GelMA under ultraviolet radiation in the presence of a photo-initiator. The GelMA/PAM biohybrid hydrogel simultaneously possessed the advantages of both PAM hydrogels and GelMA hydrogels. The GelMA block provided specific biological functions for cell adhesion and proliferation, while the flexible PAM chains reinforced the brittle gelatin network and sustain load during deformation. Compared with pure PAM hydrogel and GelMA, the GelMA/PAM biohybrid hydrogels showed enhanced compression strength (0.38 MPa) and improved elasticity (storage modulus of 1000 Pa). The GelMA/PAM biohybrid hydrogel showed a favorable degradation rate and sustained protein release. In vitro cell culture showed that the chondrocytes remained viable and proliferated on the biohybrid hydrogel, demonstrating that the biohybrid hydrogels had good cell adhesion and excellent biocompatibility. In a rabbit knee cartilage defect model, we evaluated the cartilage repair ability of the biohybrid hydrogel in vivo. In summary, this study demonstrated that hybridization of synthetic polymers considerably improves the performance and expands the application of the gelatin-based hydrogels. The biohybrid