Background: Breast cancer remains a leading global health problem and improved non-invasive diagnostics are needed to distinguish malignant from benign breast lesions and reduce unnecessary biopsies. Methods: We performed a systematic review and meta-analysis of studies that compared cfDNA assays in histopathology-confirmed breast cancer versus benign breast disease. A comprehensive search of PubMed, Embase, Cochrane Library, ScienceDirect, Web of Science, and Google Scholar through May 2026 identified studies meeting predefined PICO criteria. Two reviewers independently screened studies, extracted data, and assessed quality with the Joanna Briggs Institute tool. Sensitivity and specificity were used to summarize overall diagnostic performance. The random-effects model was used to calculate the pooled statistics. Results: From 1,131 citations, 15 studies met inclusion and were selected for the final qualitative analysis. Study sample sizes and methods varied widely. Reported per-study sensitivity ranged from 13% to 100% and specificity from 40% to 100%, producing substantial between-study heterogeneity and threshold effects. The pooled analysis found that cfDNA concentration distinguished breast cancer from benign lesions with a sensitivity of 75% (95% CI, 63–88%) and a specificity of 77% (95% CI, 69–85%). Plasma-based methylation, mutation-targeted, and fragmentomics assays generally clustered toward higher specificity than crude total-cfDNA concentration measures, while serum and simple concentration assays showed more variable and often lower specificity. Conclusions: cfDNA assays show biologic promise and assay-dependent diagnostic accuracy for discriminating breast cancer from benign lesions, but current evidence is heterogeneous.