Development of a nerve guidance conduit (NGC) is critically required for replacing the gold standard, autograft, in the repair of peripheral nerve (PN) injury with a long transecting gap. In the present study, an engineered cryogel-based NGC composed of methacrylated gelatin (MeGel), methacrylated hyaluronic acid (MeHA), and 4 arm poly(ethylene glycol) acrylate (4Arm-PEG-acrylate) was fabricated by utilizing a free radical cryopolymerization method. In vitro studies showed that the MeGel/MeHA/4Arm-PEG-acrylate hybrid cryogel provided a favorable surface and microenvironment for the adhesion, proliferation, and phenotype maintenance of rabbit Schwann cells. A 10 mm long transection in the rat sciatic nerve was created for in vivo studies. The results demonstrated that after the 16 weeks of repairing, the cryogel-based NGC supported axon regeneration and remyelination with comparable myelinating diameter and density of the regenerated nerve fibers to the autograft group. The rats with implanted cryogel-based NGC also showed sensory function recovery. This study demonstrated that our cryogel-based NGC is effective at assisting the repair of damaged PN because of its excellent structural stability, great handling convenience, and regeneration guidance capacity.