Introduction. The value of compression studies and applications in hypertrophic scar (HTS) treatment is often undermined due to the lack of ideal controls, patient compliance, and clear action mechanisms. Objective. This study assesses the genome-wide compression effects on scars under well-controlled conditions. Materials and Methods. An automated pressure delivery system (APDS) applied controlled doses of pressure to scars in a red Duroc swine HTS model. Full-thickness wounds were created by a skin grafting instrument on each animal’s bilateral flanks and were observed through reepithelialization and scar development. On day 70, the APDSs were mounted on the developed scars; right flank scars received a pressure of 30 mm Hg, while left flank scars received APDSs with no pressure (sham) for 2 weeks. A genome-wide assessment of compression effect on transcription in scar specimens before (early), shortly after (mid), and long after (late) compression initiation were performed. Results. Analysis of early-phase biopsies showed similar transcriptome profiles, which diverged thereafter in gene numbers and functions between compression- and sham-treated scars in the mid phase. The majority of these changes persisted in the late-phase scar samples. Canonical pathway analysis of differentially regulated genes resulted in an almost identical list of pathways during the early phase prior to compression. In the mid and late phases after compression, many of the identified pathways shifted in significance, and new pathways such as calcium signaling and cholesterol synthesis emerged. Conclusions. Compression modulates transcription and affects multiple biological functions associated with an improved scar appearance.