Abstract Background Neuraminidase inhibitors (NAIs) are the only effective therapy for influenza, but few studies have assessed the impact of early NAI therapy on clinical outcomes or the patient-level factors that determine early NAI delivery in hospitalized patients. Methods We conducted a retrospective cohort study of all adults hospitalized in a metropolitan tertiary care hospital with confirmed influenza from April 2009 to March 2014. We performed logistic regression to determine patient-level factors that were associated with early NAI therapy. We analyzed the association of early NAI therapy with hospital lengths of stay (LOS) and in-hospital mortality rates using linear and logistic regression, respectively. Results In total, 699 patients were admitted with influenza during the 5 influenza seasons. Of those, 582 (83.4%) received NAI therapy; however, only 26.0% received the first dose within 6 hours of hospitalization (early NAI). Patients with diabetes mellitus or pregnancy were more likely to receive early NAI (P = .01, vs. P < .001 in those without these conditions), as were those reporting fever or myalgias at presentation (P = .002, vs. P = .005 without). Immunosuppressed patients were less likely to receive early NAI (P = .04). Early NAI was associated with shorter hospital LOS (P < .001). No patients died in the early NAI group, compared to 18 deaths in the 399 patients receiving NAI after 6 hours (4.5%) and 4 deaths in the 116 patients not receiving NAI (3.4%). Conclusions Over multiple influenza seasons, early NAI therapy was associated with shorter LOS in patients admitted with influenza. This suggests that efforts should focus on facilitating earlier therapy in patients with suspected influenza. Over 5 influenza seasons, the initiation of neuraminidase inhibitor therapy within 6 hours of hospitalization was associated with shorter lengths of stay, as compared to delayed initiation of therapy, in patients admitted with influenza.