To determine the efficacy of supramolecular salicylic acid combined with doxycycline on acne, totally 70 patients with acne treated in our dermatology department from May 2020 to May 2021 were enrolled and randomized (1:1) into control or experimental groups using the random number table method. The control group was given doxycycline for oral administration while the experimental group was given oral doxycycline combined with supramolecular salicylic acid for topical administration. The overall effective rate of treatment was significantly higher in the experimental group versus control group (97.14% vs. 82.86%, P<0.05). Patients in the control group had significantly longer mean acne regression time after treatment versus experimental group (P<0.05). After treatment, patients in the experimental group had significantly lower self-rating depression scale (SDS) scores and self-perceived burden (SPB) scores than the control group, while Short Form 36-item health survey (SF-36) scores were significantly higher than the control group (P<0.05). The overall incidence of adverse reactions was significantly lower in the experimental group versus control group (5.71% vs. 17.14%, P<0.05). Supramolecular salicylic acid in combination with doxycycline in the treatment of patients with acne is an optimal option, as it could better promote acne regression, reduce the level of depression and reduce the patient's self-perceived burden.