Background: Systemic thrombolysis (ST) is the guideline-recommended treatment for high-risk pulmonary embolism (PE), although catheter-directed thrombolysis (CDT) may provide a treatment alternative associated with lower rates of bleeding. Furthermore, the treatment trends and outcomes among those with high-risk PE according to treatment assignments of no lytic therapy (NLT), ST, and CDT are underreported. Methods: Patients hospitalized for high-risk PE between 2016 and 2019 were identified by administrative claims codes from the National Readmission Database. Therapy assignment was similarly defined by administrative codes, then stratified into NLT, ST, and CDT cohorts to report patient characteristics, care settings, and clinical outcomes. The primary outcome was in-hospital mortality with rates adjusted for patient and hospital characteristics using multivariable logistic regression. Secondary outcomes included intracranial hemorrhage (ICH), gastrointestinal bleeding (GIB), and 90-day readmission. Over the years of interest, trends in lytic treatment along with concomitant use of mechanical or surgical thrombectomy were reported. Results: Among 74,516 patients with high-risk PE, 61,569 (82.6%) received NLT, 8445 (11.3%) received ST, and 4502 (6.04%) received CDT. The NLT subgroup, relative to ST and CDT, tended to be older (66.1 ± 15.4, 62.8 ± 15.3, and 63.4 ± 14.4; p < 0.001) and more frequently women (56.0%, 54.4%, and 51.3%; p < 0.001), respectively. The unadjusted in-hospital mortality rate was highest for ST (18.8%, 34.1%, and 18.3% for NLT, ST, and CDT, respectively; p < 0.001) and persisted after multivariable adjustment (adjusted odds ratio (aOR) 0.43; 95% CI 0.38–0.49; p < 0.0001) of in-hospital mortality for CDT relative to ST. The unadjusted rate of ICH or GIB was lowest for NLT (1.0%, 2.0%, and 0.6% for NLT, ST, and CDT, respectively; p < 0.001). CDT, relative to ST, was associated with reduced odds of ICH (aOR 0.32; 95% CI 0.18–0.55; p < 0.0001) and GIB (aOR 0.78; 95% CI 0.62–0.98; p < 0.0001). Readmissions were highest for NLT (21.7%, 9.6%, and 12.1% for NLT, ST, and CDT, respectively; p < 0.001). CDT was associated with a higher incidence of 90-day readmission relative to ST (aOR 1.32; 95% CI 1.10–1.57; p < 0.001). From 2016 to 2019, individual treatment trends were not significantly different, although NLT tended to be offered among smaller and rural hospitals. Rates of concomitant thrombectomy were low in all three treatment groups. Conclusions: Among a large, contemporary, US cohort with high-risk PE, over 80% of patients did not receive any form of thrombolysis. High-risk PE that did receive systemic thrombolysis was associated with the highest rates of in-hospital mortality, suggesting opportunities to study the implementation of lytic and nonlytic-based treatments to improve outcomes for those presenting with high-risk PE.