The invention relates to a compound topical combination drug for treatment of acne and a preparation method thereof. The compound topical combination drug is characterized in that a matrix carrier of the compound topical drug contains the following active components (by weight percent): 0.01-2.5 percent of retinoid acid, 0.2-10 percent of two antibacterial drugs, and 0.01-1 percent of estrogen or1-10 percent of spironolactone. The applied dosage forms are gel, ointment, liniment, film, film coating agent, sprays and the like, and the gels, the ointment, the liniment and the film coating agent are preferred. The preparation method comprises the following steps: dissolving the main drug with a suitable solvent system, adding into the matrix, adding corresponding and necessary auxiliary materials and mixing to obtain the combination drug. The invention has the advantages that: the main drug contains the retinoid acid, two antibacterial drugs, and estrogen or spironolactone, the prescription combination is scientific so as to simultaneously play three or more therapeutic effects (adjusting the sebaceous gland function, resisting keratinization abnormalities, inflammation and microbe,performing like estrogen and the like), and thereby curing the acne more comprehensively and intensively. Humectants such as carbamide is added in the drug so as to reduce side effects such as skin dryness, desquamation, erythema and the like, and no adverse reactions such as stimulus and allergy are caused during animal experiments. The preferred drug dosage forms have strong coupling effect with the skin, are easy to be applied and spread, can not pollute the clothes, and have good patient compliance and accurate clinical therapeutic effect.