Background: Cardiac involvement represents a major determinant of morbidity and mortality in patients with muscular dystrophies (MDs). Evidence supporting guideline-directed heart failure (HF) therapy in this population remains limited. We aimed to retrospectively assess the effectiveness and tolerability of sodium–glucose co-transporter 2 inhibitors (SGLT2i) in patients with MDs and a previous history of HFrEF, HFpEF and HFmrEF and/or echocardiographic evidence of an LVEF < 50% Methods: In this retrospective, single-center study, we enrolled consecutive patients with MD treated with empagliflozin or dapagliflozin between October 2021 and October 2024. Comprehensive clinical, laboratory, echocardiographic, and functional data were collected at a baseline (V1) and at follow-up (V3) visit to evaluate longitudinal changes. Results: Twenty-four patients (mean age 42 ± 16 years; 92% male) were included, with a median follow-up of 418 ± 104 days. SGLT2i therapy was well tolerated; one patient discontinued treatment due to a urinary tract infection. LVEF significantly improved from 41 ± 5% to 44 ± 6% (p = 0.005). FSS decreased from 36 to 30 (p < 0.001), indicating improved functional capacity. Background HF therapy was intensified over time, with increased prescription of mineralocorticoid receptor antagonists (21% vs. 52%; p = 0.039) and β-blockers (67% vs. 91%). The interval between MD diagnosis and cardiomyopathy onset independently predicted LVEF improvement (β = 0.17; p = 0.012). Conclusions: In patients with MDs and HF, SGLT2i therapy was safe and associated with a modest but significant improvement in LVEF, reduced fatigue, and enhanced prescription of guideline-directed HF therapy. These findings support the potential role of SGLT2i in this high-risk population and warrant confirmation in larger prospective studies.