Acne vulgaris (AV) is a multifactorial sebaceous glands disorder resulting from androgen receptor activation associated with follicular colonization by bacteria. Oral administration of the androgenic antagonist flutamide (FLU) and the antibacterial dapsone (DAP) may cause several side effects. Hence, this study aimed to design a topical microemulsion (ME) combining these drugs to manage AV. Drugs solubility was examined in different oils, surfactants and cosurfactants. Pre-formulation and compatibility studies were performed. The selected MEs were characterized to determine one ME to be investigated regarding stability, and skin irritation as well as antibacterial, anti-inflammatory, and anti-acne activities. Based on the in vitro characterization of the selected MEs, o/w ME (F1) based on 15 % w/w oils (tea tree oil (TTO)/rose oil (RO)) and 40%w/w of tween 20 as surfactant together with transcutol p as co-surfactant was chosen as the optimized ME. The results revealed that F1 showed acceptable pH, viscosity, conductivity, and droplet size (172.6 ± 9.7 nm). The in vitro release and ex vivo permeation of DAP and FLU were efficiently enhanced by their combination in F1. Moreover, F1 exhibited considerable antimicrobial activity against Staphylococcus aureus (S. aureus). Topical application of F1 resulted in low expression levels of interleukin 1β associated with a reduction in the number of androgenic receptors (AR). In conclusion, F1 could be suggested as a combination topical therapy to control AV via its anti-inflammatory, anti-acne, and antimicrobial activities.