Chronic overuse of antibiotics has led to an age where some microorganisms are no longer susceptible to any known antibiotic. Of particular concern to clinicians is one type of antibiotic-resistant bacteria that contributes to the majority of hospital acquired surgical site infections and is establishing an increased presence in community acquired infections as well: methicillin-resistant Staphylococcus aureus (MRSA). One promising substance that has been shown to inhibit the growth of S. aureus in vitro is manuka honey (MH). However, not much is known about the role MH may play in the inhibition of initial wound infection or how it may alter the course of skin and soft tissue infections (SSTIs) in a living organism. To explore this aspect, we used an established epicutaneous mouse model of infection which involved pretreating mice with MH or a MH-based product called MEDIHONEY®, followed by the creation of a small wound on each ear using a needle inoculated with either a methicillin-susceptible strain of S. aureus (MSSA) or MRSA. Results were interpreted at 24, 48, and 72 hours post-inoculation by 1) superficial appearance to qualitatively track wound development and progression, 2) histology to evaluate inoculated tissue for signs of inflammation, and 3) RT-qPCR to compare the expression levels of several inflammatory cytokines involved in the early inflammatory response between groups. Data collected in this study did not provide substantial evidence to support the supposition that MH or MEDIHONEY® has a significant impact on the early course of SSTIs. Further investigations should focus on the potential application of MH and MH-based products as a treatment option for established SSTIs rather than a prophylactic measure.