Large rotator cuff tendon injuries pose a dual clinical challenge: poor inherent healing capacity and high mechanical demands. To address this, we have developed a bifunctional scaffold that combines a slow-degrading, mechanically robust polyurethane core coated with tendon-derived extracellular matrix (ECM) extract to provide both structural support and regenerative cues. In a rabbit model of supraspinatus tendon injury, this ECM-polyurethane scaffold facilitated healing of critical-sized defects, resulting in aligned, tendon-like tissue with improved biomechanical properties. This study further explored the tendon healing mechanisms of the ECM-polyurethane scaffold in a rabbit model of large supraspinatus tendon injury using transcriptomic and qPCR analyses. At one month post-surgery, while both ECM-coated and uncoated polyurethane scaffolds initially provoked similar inflammatory responses when compared to healthy tendon, their healing pathways diverged significantly. The control polyurethane scaffold activated pathways associated with adipose tissue development, a non-functional outcome, whereas the ECM-coated scaffold actively directed healing toward tendon regeneration. These results demonstrate that the ECM coating is the critical factor driving divergent healing responses in polyurethane scaffolds, even though their underlying biomechanical properties are similar. This underscores the importance of combining biomechanical reinforcement with biologically active regenerative signals for effective regeneration of tendon and other load-bearing tissues.