Background: Elevated ALP and LDH levels have been associated with worse prognosis in several malignancies; however, their role in MBC remains unclear. We aim to explore the prognostic impact of ALP and LDH levels at baseline and after 12 weeks of first line therapy in MBC patients (pts). Methods: This retrospective study analyzed 396 consecutive pts with a diagnosis of MBC, treated between 2007 and 2017 at the Oncology Department of Udine (Italy). The prognostic impact of elevated baseline ALP ( > 104 U/L) and LDH ( > 480 U/L), and their changes after 12 weeks of first line treatment were investigated through Cox regression. Results: After a median follow-up of 52.8 months, median overall survival (OS) was 30.9 months and median progression free survival (PFS) was 9.2 months. Pts with baseline elevated ALP or LDH were 33.8% (126/373) and 31.5% (70/222), respectively. The 16.9% (37/219) of pts had both elevated ALP and LDH. By univariate analysis, pts with baseline elevated levels of ALP (HR 1.82, 95% CI: 1.39–2.38, p < .0001), LDH (HR 2.27, 95% CI: 1.58–3.24, p < .0001) or both (HR 3.36, 95% CI: 2.15–5.27, p < .0001; vs pts with normal ALP and LDH) had worse OS. By multivariate analysis, after adjustment for molecular profiles, performance status (PS), number of sites, central nervous system (CNS), liver, and bone involvement, a worse prognosis was confirmed for pts with high baseline levels of LDH (HR 1.74, 95% CI: 1.12–2.69, p = .013) and elevated levels of both ALP and LDH (HR 2.84, 95% CI: 1.64–4.91, p < .0001; vs pts with normal ALP and LDH). When considering ALP and LDH levels after 12 weeks of first line treatment, by multivariate analysis, pts with stably elevated LDH had worse OS (HR 2.61, 95% CI: 1.15–5.9, p = .021) and PFS (HR 2.88, 95% CI: 1.40–5.89, p = .004) compared to pts with stably normal LDH. Conclusions: High pre-treatment levels of LDH or both ALP and LDH or stably high LDH levels during first line treatment are negative and independent prognostic factors also when adjusted for liver and bone localizations. The present study paves the way to a prospective validation of ALP, LDH and their combination as promising cost-effective biomarkers.