Abstract: Objective To evaluate the effect of abemaciclib combined with everolimus on hormone-receptor positive/human epidermal growth factor receptor 2-negative（HR⁺/HER2^-） advanced breast cancer. Methods A total of 155 HR⁺/HER2^- advanced breast cancer patients admitted to Luoyang Maternal and Child Health Hospital from January 2022 to January 2024 were enrolled. They were randomly divided into two groups. The control group received a combination of everolimus and endocrine therapy, while the intervention group received abemaciclib in addition to the regimen given to the control group. Both groups were treated for 8 cycles, with 21 days constituting one cycle. The clinical efficacy was assessed after 8 cycles of treatment. The levels of tumor markers carbohydrate antigen 153（CA153）, carcinoembryonic antigen（CEA）, human epidermal growth factor receptor 2（HER2/neu）, lymphocyte subpopulation indicators, estrogen indicators estrone（E₁）, estradiol（E₂）, estrogen receptor（ER）, and adverse reactions were assessed during treatment after 4 and 8 cycles of treatment. Survival rates were documented during follow-up. All data were compared between the two groups. Results The disease control rate（DCR） in the intervention group was higher than that in the control group（P< 0.05）. After 4 cycles and 8 cycles of treatment, the levels of CEA, CA153, HER2/neu, CD8⁺, E₁, E₂ and ER in both groups were decreased compared with those before treatment, and the levels in the intervention group were lower than those in the control group at the corresponding time points（all P< 0.05）. After 8 cycles, the levels of CD3⁺ and CD4⁺ were increased compared with baseline, and were higher in the intervention group than those in the control group at the corresponding time points（all P< 0.05）. There was no significant difference in the overall incidence of adverse reactions, including headache, gastrointestinal reactions and insomnia between the two groups（P> 0.05）. The progression-free survival rate and overall survival rate in the intervention group were both higher than those in the control group（P< 0.05）. Conclusion Abemaciclib in combination with everolimus demonstrates definite clinical efficacy in the treatment of HR⁺/HER2^- advanced breast cancer. It can effectively improve the serum levels of tumor markers in patients, with a favorable overall safety profile and manageable adverse reactions, thus holding good value for clinical application and promotion.