Background: Nerve repair using photochemically bonded human amnion nerve wraps can result in superior outcomes in comparison with standard suture. When applied to nerve grafts, efficacy has been limited by proteolytic degradation of bonded amnion during extended periods of recovery. Chemical crosslinking of amnion before bonding may improve wrap durability and efficacy. Methods: Three nerve wraps (amnion, cross-linked amnion, and cross-linked swine intestinal submucosa) and three fixation methods (suture, fibrin glue, and photochemical bonding) were investigated. One hundred ten Lewis rats had 15-mm left sciatic nerve gaps repaired with isografts. Nine groups (n = 10) had isografts secured by one of the aforementioned wrap/fixation combinations. Positive and negative control groups (n = 10) were repaired with graft and suture and no repair, respectively. Outcomes were assessed using sciatic function index, muscle mass retention, and histomorphometry. Statistical analysis was performed using analysis of variance and the post hoc Bonferroni test (p < 0.05). Results: Cross-linking improved amnion durability. Photochemically bonded crosslinked amnion recovered the greatest sciatic function index, although this was not significant in comparison with graft and suture. Photochemically bonded crosslinked amnion recovered significantly greater muscle mass (67.3 ± 4.4 percent versus 60.0 ± 5.2 percent; p = 0.02), fiber diameter, axon diameter, and myelin thickness (6.87 ± 2.23 μm versus 5.47 ± 1.70 μm; 4.51 ± 1.83 μm versus 3.50 ± 1.44 μm; and 2.35 ± 0.64 μm versus 1.96 ± 0.47 μm, respectively) in comparison with graft and suture. Conclusion: Light-activated sealing of cross-linked human amnion results in superior outcomes when compared with conventional suture.