Background: We aim to understand whether all patients with hormonal receptor (HR)-positive (+)/human epidermal growth factor receptor-2 (HER2)-negative (−) metastatic breast cancer (MBC) should receive cyclin D-dependent kinase (CDK) 4/6 inhibitor-based therapy as a first-line approach. Methods: A network meta-analysis (NMA) using the Bayesian hierarchical arm-based model, which provides the estimates for various effect sizes, were computed. Results: First-line treatment options in HR+/HER2− MBC, including CDK 4/6 inhibitors combined with aromatase inhibitors (AIs) or fulvestrant (F), showed a significantly longer progression-free survival (PFS) in comparison with AI monotherapy, with a total of 26% progression risk reduction. In the indirect comparison across the three classes of CDK 4/6 inhibitors and F endocrine-based therapies, the first strategy resulted in longer PFS, regardless of specific CDK 4/6 inhibitor (HR: 0.68; 95% CrI: 0.53–0.87 for palbociclib + AI, HR: 0.65; 95% CrI: 0.53–0.79 for ribociclib + AI, HR: 0.63; 95% CrI: 0.47–0.86 for abemaciclib + AI) and patient’s characteristics. Longer PFS was also found in patients with bone-only and soft tissues limited disease treated with CDK 4/6 inhibitors. Conclusions: CDK 4/6 inhibitors have similar efficacy when associated with an AI in the first-line treatment of HR+ MBC, and are superior to either F or AI monotherapy, regardless of any other patients or tumor characteristics.