The purpose of this study is to evaluate whether early initiation of catheter-directed thrombolysis (CDT) in patients presenting with acute pulmonary embolism is associated with improved in-hospital outcomes. A retrospective cohort was extracted from the 2016–2019 National Inpatient Sample database, consisting of 21,730 weighted admissions undergoing CDT acute PE. From the time of admission, the sample was divided into early (48 h). Outcomes were measured using regression analysis and propensity score matching. No significant differences in mortality, cardiac arrest, cardiogenic shock, or intracranial hemorrhage (p > 0.05) were found between the early and late CDT groups. Late CDT patients had a higher likelihood of receiving systemic thrombolysis (3.21 [2.18–4.74], p < 0.01), blood transfusion (1.84 [1.41–2.40], p < 0.01), intubation (1.33 [1.05–1.70], p = 0.02), discharge disposition to care facilities (1.32 [1.14–1.53], p < 0.01). and having acute kidney injury (1.42 [1.25–1.61], p < 0.01). Predictors of late intervention were female sex, nonwhite race, and weekend admission (p < 0.01). This study represents a comprehensive evaluation of outcomes associated with the time interval for initiating CDT, revealing reduced morbidity with early intervention. Additionally, it identifies predictors associated with delayed CDT initiation. The broader ramifications of these findings, particularly in relation to hospital resource utilization and health disparities, warrant further exploration.