Background/Objectives: D-dimer, a fibrin degradation product, is associated with tumor growth and metastasis. In breast cancer, high concentrations of D-dimer are linked to more advanced disease stages and metastatic spread. This research aimed to examine the relevance of D-dimer levels in estrogen and progesterone hormone receptor (HR)-positive breast cancer. Methods: This retrospective single-center cohort study included patients with HR-positive breast carcinoma who underwent adjuvant or palliative radiotherapy in Türkiye. Pre- and post-radiotherapy blood test results, including D-dimer levels, were required. D-dimer, lymphocyte percentage, and interleukin-6 levels were measured for evaluation. All statistical analyses were performed using R software (version 4.4.2) to evaluate associations between D-dimer levels and other laboratory parameters. Univariate and multivariate Cox proportional hazards regression were performed to identify prognostic factors for progression-free survival (PFS) and overall survival (OS). Statistical significance was defined as p < 0.05. Results: Elevated D-dimer levels were associated with worse Eastern Cooperative Oncology Group performance status, advanced disease stages, metastasis, elevated IL-6 and CRP levels, and lower lymphocyte counts. Pre-RT D-dimer was a strong prognostic factor. Patients with D-dimer ≤ 0.3 µg/mL showed significantly superior OS and PFS (>60 months; p < 0.001), with only one event, and this remained significant in multivariate analysis (OS: HR 4.55, 95% CI 1.89–11.3; p = 0.002; PFS: HR 3.43, 95% CI 1.54–7.8; p = 0.004). Similarly, D-dimer ≤ 0.5 µg/mL was associated with improved OS (4/72 vs. 19/40 events; p < 0.001) and longer PFS, confirmed in multivariate analysis (OS: HR 4.37, 95% CI 1.72–9.86; p = 0.002; PFS: HR 3.88, 95% CI 1.67–9.1; p = 0.003), whereas levels > 0.5 µg/mL predicted worse outcomes. Using a 0.65 µg/mL cutoff, patients with D-dimer > 0.65 µg/mL had significantly shorter OS (median 25.5 months; 95% CI, 18–NA) compared with those ≤0.65 µg/mL (median not reached; p < 0.001), and this remained independently significant (OS: HR 5.10, 95% CI 1.9–13.6; p < 0.001; PFS: HR 4.68, 95% CI 1.83–11.9; p = 0.002). Conclusions: D-dimer is an accessible, non-invasive biomarker with predictive and prognostic significance in HR-positive breast cancer. Elevated D-dimer levels are suggestive of a more aggressive disease and poorer survival outcomes. This has the potential to facilitate early assessment of treatment efficacy and disease progression. This study has several limitations. Its retrospective, single-center design may introduce selection bias and limit generalizability. Although the sample size was sufficient to detect significant associations, validation in larger, multi-center cohorts is warranted to confirm the prognostic value of D-dimer.