As the use of laparoscopic surgery has become more widespread in recent years, the need has increased for minimally-invasive surgical devices that effectively cut and coagulate tissue with reduced tissue trauma. Although electrosurgery (ES) has been used for many generations, newly-developed ultrasonic devices (HARMONIC® Blade, HB) have been shown at a macroscopic level to offer better coagulation with less thermally-induced tissue damage. We sought to understand the differences between ES and HB at a microscopic level by comparing mRNA transcript and protein responses at the 3-day timepoint to incisions made by the devices in subcutaneous fat tissue in a porcine model. Samples were also assessed via histological examination. ES-incised tissue had more than twice as many differentially-expressed genes as HB (2,548 vs 1,264 respectively), and more differentially-expressed proteins (508 vs 432) compared to control (untreated) tissue. Evaluation of molecular functions using Gene Ontology showed that gene expression changes for the energized devices reflected the start of wound healing, including immune response and inflammation, while protein expression showed a slightly earlier stage, with some remnants of hemostasis. For both transcripts and proteins, ES exhibited a greater response than HB, especially in inflammatory mediators. These findings were in qualitative agreement with histological results. This study has shown that transcriptomics and proteomics can monitor the wound healing response following surgery and can differentiate between surgical devices. In agreement with clinical observations, electrosurgery was shown to incur a greater inflammatory immune response than an ultrasonic device during initial iatrogenic wound healing.