The complexity of modern combat wounds necessitates multiple debridement surgeries before definitive closure, making an understanding of the biological processes involved in wound healing essential for improving clinical outcomes. This study investigates the transcriptomic differences between large and small wounds, aiming to determine if clinical decision support tools developed for small wounds are applicable to larger wounds. The cohort for this study, known as WoundVAC and WounDx, includes both military and civilian extremity wounds treated at Walter Reed Army Medical Center and Grady Memorial Hospital. Clinical and biospecimen data were collected at each debridement. A total of 173 tissue samples from 45 wounds that successfully healed upon definitive closure were sequenced. These wounds were categorized by size: small wounds with a volume of less than 1000 mm³ and large wounds with a volume of 1000 mm³ or greater. Samples were further grouped by time points post-injury (3-5, 6-8, 9-11, and 12-14 days). Differential gene expression analysis was performed using DESeq2, and enriched biological processes and functions were identified using g:Profiler. The analysis focused on Gene Ontology (GO) terms relevant to wound healing, including extracellular matrix (ECM) and collagen, immune response, membrane processes, and signaling. Results indicated significant differences in gene expression between large and small wounds, especially at early and late time points. Notably, large wounds exhibited a peak in immune and signaling downregulation between 9 to 11 days post-injury, while small wounds showed this peak at 3 to 5 days post-injury. Immune and signaling motifs displayed both up and downregulation across various time points, suggesting complex regulatory mechanisms at play. ECM, collagen, and membrane processes were less differentially expressed compared to immune and signaling processes. The findings highlight that wound size impacts the trajectory of gene expression during healing, which may influence the effectiveness of clinical decision support tools. This study emphasizes the need for further investigation into the specifics of immune signaling and the differences between failed and healed wounds to enhance wound management strategies. In conclusion, understanding the differential gene expression in large versus small wounds can inform the development of more tailored and effective clinical decision support tools for wound care, ultimately improving patient outcomes in both military and civilian settings.