Superficial pyoderma is a common skin disease caused by coagulase-positive staphylococci, especially Staphylococcus pseudintermedius and Staphylococcus aureus. The therapeutic use of antibiotics has many unwanted impacts, and the incidence of drug-resistant strains is increasing. Therefore, the aims of this non-inferior randomized controlled trial were to determine the effectiveness of 5% w/w clove essential oil lipid-based spray in treating superficial pyoderma in dogs, compared to 2% w/v chlorhexidine gluconate spray, and to evaluate the potential skin irritation of the clove oil spray formulation. The results demonstrated that the therapeutic effect of the clove essential oil spray was non-inferior to chlorhexidine gluconate spray when applied topically 2 times a day for 15 days. The clinical lesion index scores of dogs treated with clove essential oil spray were reduced by 66.87% on day 10 and 83.73% on day 15 after initiating treatment, with no adverse effects. The skin irritation test showed that clove essential oil spray did not induce erythema or edema at the tested sites. This report suggests that a lipid-based clove essential oil spray formulation is a suitable alternative topical treatment for canine superficial pyoderma.