Background: Hyperlipidemia, a key risk factor for cardiovascular disease, is characterized by elevated low‐density lipoprotein cholesterol (LDL‐C), triglycerides, and reduced high‐density lipoprotein cholesterol (HDL‐C). Cholesteryl ester transfer protein (CETP) inhibitors, such as anacetrapib, obicetrapib, evacetrapib, dalcetrapib, and torcetrapib, aim to improve lipid profiles by increasing HDL‐C and reducing LDL‐C, but their comparative efficacy remains unclear.Methods: This systematic review and frequentist network meta‐analysis, conducted per PRISMA‐NMA guidelines, included 33 randomized controlled trials (RCTs) involving 120,292 adults with hyperlipidemia. We compared CETP inhibitors, alone or with statins, against placebo or other lipid‐lowering therapies. Primary outcome was LDL‐C reduction; secondary outcomes included HDL‐C, triglycerides, and total cholesterol changes. Random‐effects models calculated mean differences (MD) with 95% confidence intervals (CI), and P‐scores ranked interventions.Results: Atorvastatin + obicetrapib showed the largest reduction in LDL‐C levels (MD: −69.00, 95% CI: −95.96 to −42.04, p < 0.0001), followed by rosuvastatin + obicetrapib (MD: −60.70, 95% CI: −99.28 to −22.12, p = 0.0020). Atorvastatin + obicetrapib yielded highly significant increase in HDL‐C levels (MD: 149.90, 95% CI: 121.70 to 178.10, p < 0.0001), but rosuvastatin + obicetrapib showed the greatest increase (MD: 158.90, 95% CI: 118.59 to 199.21, p < 0.0001) and obicetrapib monotherapy (MD: 139.00, 95% CI: 129.05 to 148.96, p < 0.0001), while rosuvastatin + evacetrapib led triglyceride reductions (MD: −31.70 mg/dL). Rosuvastatin was most effective for total cholesterol (MD: −31.60 mg/dL).Conclusion: CETP inhibitors, particularly anacetrapib and obicetrapib combined with statins, significantly improve lipid profiles, offering potential therapeutic benefits for hyperlipidemia management and cardiovascular risk reduction.Trial Registration: The study was registered with PROSPERO to ensure transparency and adherence to methodological rigor (Registration ID: CRD420250652666).