Objective To explore the efficacy and safety of doxycycline sequential low-dose isotretinoin in the treatment of refractory papulopustular acne. Methods A total of 68 patients with refractory papulopustular acne admitted to Huzhou Nanxun People's Hospital from October 2024 to October 2025 were selected, and they were divided into the reference group and the experimental group by the random number table method, with 34 patients in each group. The reference group was treated with doxycycline, and the experimental group was treated with doxycycline sequential low-dose isotretinoin. The treatment effect, inffammatory factor levels, facial aesthetics, quality of life and adverse event rate were compared between the two groups. Results The total effective rate of treatment in the experimental group (97.06%) was higher than that in the reference group (82.35%) (P<0.05). The levels of TNF-α, IL-6 and hs-CRP in the experimental group after treatment were lower than those in the reference group (P<0.05). The NRS score of the experimental group after treatment was higher than that of the reference group, and the DLQI score was lower than that of the reference group (P<0.05). The incidence of adverse events in the experimental group (2.94%) was lower than that in the reference group (20.58%) (P<0.05). Conclusion For refractory papulopustular acne, sequential low-dose isotretinoin on the basis of doxycycline can effectively improve efffcacy and inffammatory indicators, help to improve facial aesthetics and quality of life of patients, while the incidence of adverse events sfter treatment is low, demonstrating both good efffcacy and safety.