Pulmonary embolism (PE) is a significant cardiovascular condition requiring stratified management, particularly in intermediate-high-risk cases where hemodynamic instability is absent but markers of severity are present. This report presents the case of a 54-year-old female with malignancy-associated intermediate-high-risk PE complicated by severe hypoxemic respiratory failure and high bleeding risk. The patient underwent multiple advanced interventions, including percutaneous thrombectomy, catheter-directed thrombolysis, and reduced-dose systemic thrombolysis, due to persistent thrombotic burden and respiratory insufficiency. The case underscores the challenges of managing PE in the context of advanced malignancy and comorbidities, necessitating a balance between thrombosis resolution and minimizing hemorrhagic risk. The therapeutic approach was partially guided by the "MOPETT trial" findings, demonstrating the efficacy and safety of reduced-dose thrombolysis in moderate PE cases. Despite achieving significant improvements in respiratory function, the patient's advanced-stage malignancy and declining functional status ultimately limited oncological treatment options, transitioning care to a palliative focus. This case emphasizes the critical role of individualized therapeutic strategies that address both the acute thrombotic event and the broader oncological context, aiming to optimize patient outcomes while considering quality of life and palliative care needs. It also highlights the importance of multidisciplinary collaboration in managing complex PE cases.