In recent years, nanotechnology and the subsequent production of nanoparticles have developed excellent methods for medical applications, including wound healing. One of these nanoparticles is bentonite nanoparticles (BNPs) which show high ability in tissue engineering. But our knowledge of its effectiveness in wound healing is based on little data. Therefore, the main purpose of this study was to evaluate the wound healing ability of BNPs and in the next step the suitability of honey as a solvent for these nanoparticles. Methods: In this experimental study, an excisional wound injury model was developed in adult male BALB/c mice (n = 60) by creative two equal-sized wounds (5 mm) on either side of their back midline. The animals were allocated into five groups (n = 12 each) as untreated control (U), honey (H), polyethylene glycol (P), and (BNPs) dissolved in honey or polyethylene glycol (H + BNPs, P + BNPs). Animals have received their relative topical treatments twice per day for 14 consecutive days. Tissue sampling was carried out on days 4, 7, 10, and 14. The tissue sections were stained with hematoxylin and eosin and Trichrome-Masson staining methods. The histomorphological parameters including inflammatory cells infiltration, fibroblasts, re-epithelialization, granulation formation, and collagenases were evaluated in all tissue sections. Data were analyzed by SPSS 16 software. Comparison between the groups was performed by one-way analysis of variance following Tukey's post-hoc test. Compared to the control group, BNPs showed significant wound healing activities with lower inflammatory cells infiltration, higher fibroblastosis and new epithelium thickness, and greater granulation area and collagen fibers density in the ulcer bed. In addition, honey as a solvent synergistically increased the wound healing activity of the studied nanoparticle. These results for the first time are clearly showing that BNPs have a promising wound healing activity, especially when applied with honey concurrently.