Background: Staphylococcus aureus (SA) is a key pathogenic component of the chronic rhinosinusitis (CRS) microbiome and is associated with increased disease severity and poor postoperative outcomes. Probiotic treatments potentially offer a novel approach to the management of pathogenic bacteria in these recalcitrant patients through supporting a healthy community of commensal species. This study aims to investigate the probiotic properties of Staphylococcus epidermidis (SE) against SA in a mouse model of sinusitis. Methods: Twenty C57/BL6 mice received intranasal inoculations of phosphate buffered saline (PBS), SE, SA, or a combination of SE and SA (SE+SA) for 3 days. Following euthanasia, the mouse snouts were harvested and prepared for histological analysis. Counts of periodic acid-Schiff (PAS)-positive goblet cells were the primary outcome measure. Results: Goblet cell counts were significantly higher in both the SA and SE+SA groups compared to those receiving PBS or SE alone (p < 0.05). However, the SE+SA group demonstrated significantly lower goblet cell counts compared to the SA group (p < 0.05). Mice receiving SE alone did not show a significant difference to those receiving PBS (p > 0.05). The presence of SA postinoculation was confirmed by culture in both the SA and SE+SA groups. Conclusion: This study confirms the probiotic potential of SE against SA in a mouse model of sinusitis. Although the interactions that occur between many probiotic species and pathogens are yet to be fully understood, studies such as this support further exploration of ecologically-based treatment paradigms for the management of CRS.