Patients with hematological malignancies (HMs) are at higher risk of severe COVID-19 and secondary infections, which further complicate their outcomes. This study evaluated the impact of secondary infections (SIs) on mortality in hospitalized HM patients with SARS-CoV-2 infection and identified risk factors associated with SIs. We included 217 patients with HMs and COVID-19 admitted to a tertiary hospital in Rome, from April 2020 to September 2022. SIs occurred in 44.2% of patients, with bloodstream infections (42.7%) and respiratory infections (30.5%) being most frequent; among the latter, COVID-19-associated pulmonary aspergillosis (CAPA) was observed in 41.4% of cases. Viral reactivations, predominantly CMV, occurred in 9.2% of patients. The overall mortality rate was 29%, with higher mortality observed in patients with SIs (47.4% vs. 14.7%, < 0.01). Risk factors for SIs included severe COVID-19 (OR = 2.957, < 0.05) and prolonged hospitalization (OR = 1.095, < 0.001). Severe COVID-19 (OR = 8.229, < 0.001), intensive care unit (ICU) admission (OR = 15.232, < 0.001), chronic steroid therapy (OR = 2.803, < 0.05), SIs (OR = 2.892, < 0.05), and viral reactivation (OR = 6.269, < 0.01) were independent predictors of mortality. SIs and viral reactivations are common in patients with HMs and SARS-CoV-2 infection and significantly increase mortality, highlighting the need for timely management and preventive strategies in this vulnerable population.