Background: There is no recognized optimal second-line treatment option for advanced hormone receptor-positive (HR+) breast cancer patients with CDK4/6 inhibitor (CDK4/6i) resistance. Objectives: This work aims to identify the optimal treatment option by evaluating the efficacy of various second-line treatment options in CDK4/6i-pretreated HR+ advanced breast cancer. Subgroup analyses aim to discuss how different genetic backgrounds and clinical characteristics influence the efficacy. Design: A systematic review and network meta-analysis (NMA) was designed. Data sources and methods: A comprehensive search was conducted in Medline, Embase, and Cochrane Library for randomized controlled trials (RCTs). The primary outcome was progression-free survival (PFS), with subgroup analysis based on visceral metastasis and ESR1 mutations. Secondary outcomes were overall survival (OS), overall response rate (ORR), and clinical benefit rate (CBR). Bayesian NMA was conducted using GeMTC in R, with hazard ratios and 95% confidence intervals as effect measures. Results: Our analysis included 19 clinical trials involving 13 different treatment regimens ( n = 6621), with 14 studies ( n = 3876) reporting subgroup results for CDK4/6i-pretreated patients. Results showed that the combination of CDK4/6i and fulvestrant (Ful) was the most effective regimen for improving PFS in CDK4/6i-pretreated HR+ advanced breast cancer patients. Further subgroup analyses of visceral metastasis and ESR1 mutations consistently confirmed this finding. For OS, the combination of Bcl-2 inhibitor (Bcl-2i) and Ful was most favorable. In terms of ORR and CBR, selective estrogen receptor degraders (SERD) and CDK4/6i + ET were the most beneficial, respectively, with no significant differences among regimens in direct comparisons. Conclusion: Our analysis reveals CDK4/6i + Ful is the most effective treatment option for CDK4/6i-pretreated HR+ advanced breast cancer, particularly in patients with visceral metastases or ESR1 mutations. In addition, Bcl-2i + Ful and SERD may be potential second-line strategy options. Trial registration: This meta-analysis was registered in PROSPERO (CRD42024518926).