Background: Heart Failure (HF), a leading cause of morbidity and mortality, represents a relevant trigger for the development of frailty in the elderly. Inflammation has been reported to play an important role in HF and frailty pathophysiology. Galectin-3 (Gal-3), whose levels increase with aging, exerts a relevant activity in the processes of cardiac inflammation and fibrosis. The aim of the present study was to investigate the potential of Galectin-3 to serve as a biomarker of frailty in HF patients. Methods: 128 consecutive patients aged 65 and older with the diagnosis of systolic HF underwent a frailty assessment and blood sample collection for serum Gal-3 detection. A multivariable regression analysis and decision curve analysis (DCA) were used to identify significant predictors of frailty. Results: Frailty was present in 42.2% of patients. Age: Odds Ratio (OR) = 3.29; 95% Confidence Interval CI (CI) = 1.03–10.55, Cumulative Illness Rating Scale Comorbidity Index (CIRS-CI): OR = 1.85; 95% CI = 1.03–3.32, C-Reactive phase Protein (CRP) OR = 3.73; 95% CI = 1.24–11.22, N-terminal-pro-Brain Natriuretic Peptide (NT-proBNP): OR = 2.39; 95% CI = 1.21–4.72 and Gal-3: OR = 5.64; 95% CI = 1.97–16.22 resulted in being significantly and independently associated with frailty. The DCA demonstrated that the addition of Gal-3 in the prognostic model resulted in an improved clinical ‘net’ benefit. Conclusions: Circulating levels of Gal-3 are independently associated with frailty in elderly patients with systolic HF.