Tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, is recognized for its effectiveness in regulating glucose levels and promoting weight loss. This systematic review aims to evaluate the current evidence on the impact of tirzepatide on low-density lipoprotein (LDL) cholesterol levels in adult patients (i.e., individuals 18 years and older). A comprehensive search was conducted in the PubMed, EMBASE, and Web of Science databases through June 26, 2025, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligible studies included randomized controlled trials and observational studies in adults that reported LDL levels before and after receiving tirzepatide. The quality assessment was done using the Risk of Bias 2 tool (RoB 2, Cochrane Collaboration, London, UK) and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I). This review found that high doses of tirzepatide were associated with moderate reductions in LDL cholesterol levels, accompanied by a 19% reduction and improvements in LDL particle size. However, the findings revealed heterogeneity, with younger individuals (i.e., those 64 years and younger) exhibiting larger reductions in LDL levels compared to older individuals (i.e., those 65 years and older). Observational studies also reported heterogeneous results, limited by confounding factors and co-interventions. Overall, tirzepatide may decrease LDL cholesterol and improve its lipid profile characteristics, especially at high doses (15 mg) and in individuals with metabolic risk factors; however, variability across studies and short follow-up periods limits the ability to draw definitive conclusions. Further research is needed to establish the role of tirzepatide in controlling LDL levels and reducing cardiovascular risk.