Staphylococcus aureus is responsible for most bacterial wound infections. Antibiotics are the first-line treatment; however, their indiscriminate use led to the emergence of resistance. Alternative therapeutic options beyond antibiotic treatment are required. Our study aimed to evaluate and compare the healing parameters and antibacterial activity of Jojoba and Citrullus colocynthis oil extracts in the treatment of Staphylococcus aureus wound infections. In-vivo assessment of inflammatory biomarkers, matrix metalloproteinase and histopathological examination of Staphylococcus aureus induced wound lesions were conducted in mice. Levels of interleukin 1 and interleukin 6 were reduced, while matrix metalloproteinases ratio; MMP-1 /MMP-9 was increased after topical application of both essential oils. Citrullus colocynthis oil showed optimum wound healing compared to the other treated groups in histopathological examination. In conclusion, topical Citrullus colocynthis preparation may be a promising alternative natural dermatological application with enhanced antibacterial activity.