Abstract Background Painful, treatment-resistant wounds are prevalent among diabetic patients and significantly affect health-related quality of life (HRQOL). Topical treatments may help alleviate pain without risk of dependence or side effects. However, there is a lack of topical wound compounds targeting pain-specific receptors. One possible target is proinflammatory angiotensin 1 receptor (AT1R), which is upregulated in diabetic skin and has been implicated in nociception. Objectives We investigated the effects of topical valsartan, an AT1R antagonist, on pain (nociceptive thresholds) and gene expression changes (transcriptomics) in a swine model of diabetic wounds. Methods Eight wounds were surgically induced in diabetic, hyperglycemic Yucatan miniature swine ( n = 4). Topical AT1R antagonist was applied to wounds on one side and vehicle on the other side. Nocifensive testing was conducted at baseline, then weekly beginning 7 days after wound induction. Mechanical and thermal stimuli were applied to the wound margins until a nocifensive reaction was elicited or a predetermined cutoff was reached. After 7 weeks of testing, tissue from the dorsal horn, dorsal root ganglion, and wounds were sequenced and analyzed with DESeq2. Unbiased pathway analysis using Metascape was conducted on differentially expressed genes. Results There was no significant difference in mechanical tolerance threshold between valsartan-treated and vehicle-treated wounds ( p = .106). Thermal tolerance was significantly higher in valsartan-treated wounds compared to vehicle-treated ( p = .015). Analysis of differentially expressed genes revealed enriched pathways of interest: Interleukin–18 signaling in dorsal horn laminae IV–V and sensory perception of mechanical stimulus in wound tissue. Discussion In this study, wounds modeling diabetic ulcers were created in hyperglycemic swine and treated with a topical AT1R antagonist. Treated wounds had a higher tolerance threshold for thermal hyperalgesia but not mechanical allodynia. Pathway analysis of differentially expressed genes revealed several pathways of interest for future pain research. Although further studies are needed to confirm the findings, this study can improve nursing care of diabetic wounds by providing information about a potential future treatment that may be used to decrease pain and improve HRQOL in patients with diabetic wounds.