Background: Recent evidence found increase incidence of heart failure in leukemia patients, influenced by various factors such as the underlying disease and medication usage. Nevertheless, there remains a scarcity of data regarding the in-hospital outcome for individuals admitted for leukemia with comorbid acute decompensated heart failure. Thus, we aim to examine the impact of heart failure on clinical outcomes in leukemia patients. Methods: We utilized the 2020 U.S. National Inpatient Sample (NIS) to investigate patients admitted for leukemia with concurrent diagnosis of heart failure, identified through ICD-10 CM codes. Adjusted odds ratios (aORs) for predefined outcomes were determined using multivariable logistic and linear regression model, adjusting for comorbidities. The primary outcome assessed was inpatient mortality, while secondary outcomes included complications related to various body systems. Results: We identified 43,955 patients with a primary discharge diagnosis of leukemia. The mean age was 54.5 years; 49.7% were female. Caucasians accounted for 66%, followed by African Americans (13%). Of these, 11.86% (5,220/43,955) had a concurrent diagnosis of heart failure. In a survey multivariable logistic and linear regression model adjusting for patient and hospital factors, comorbid acute decompensated heart failure was associated with higher in-hospital mortality (aOR 1.57, 95% CI: 1.2, 1.94, p < 0.001), higher mean length of stay (Beta-coefficient 1.93; 95% CI: 0.65, 3.21, p = 0.003), mean total hospital cost (Beta-coefficient 9,472, 95% CI: 2,339, 16,604, p = 0.004), shock (aOR 2.41, 95% CI: 1.84, 3.15, p < 0.001), sepsis (aOR 1.71, 95%CI: 1.38, 2.12, p < 0.001), acute respiratory failure (aOR 2.37, 95% CI: 1.96, 2.87, p < 0.001), and acute kidney injury (aOR 1.57, 95% CI: 1.32, 1.85, p < 0.001). Conclusions: Our study revealed that hospitalized leukemia patients with concurrent heart failure experience higher risk of in-hospital mortality and various adverse in-hospital outcomes. Close monitoring of this factor during hospitalization is essential, and additional longitudinal research is warranted to fully understand this association.