Infectious endocarditis of the tricuspid valve (TV) is a common complication of intravenous (IV) drug use. Endocarditis caused by viridans streptococci can lead to heart valve vegetations, which may be life-threatening due to the potential for embolism and obstruction. The management of large valvular vegetations is often difficult due to the risks involved with open heart surgery, especially in patients with comorbid conditions. The AngioVac device (AngioDynamics Inc., Latham, NY) has been shown in rare cases to be effective at debulking vegetations without the need for invasive surgery. We present a 45-year-old male with a history of intravenous heroin use disorder, hepatitis C, spinal abscesses, and chronic anemia who experienced worsening shortness of breath, generalized weakness, bilateral lower extremity edema, dysuria with dark urine, and blood on toilet paper. Workup revealed a 4.39 × 4.35 cm tricuspid valve vegetation, severe tricuspid regurgitation (TR), acute renal failure, acute on chronic anemia, and thrombocytopenia from sepsis-induced disseminated intravascular coagulation (DIC). AngioVac was used to aspirate the vegetation and effectively reduced the size to 3.75 × 2.31 cm. Follow-up blood cultures revealed no growth after five days. This is the largest documented tricuspid valve vegetation with a successful implementation of the AngioVac to date. This therapy, in conjunction with intravenous antibiotics and hemodialysis, successfully sterilized the vegetation, prevented worsening presentation, and averted life-threatening complications, although severe tricuspid regurgitation persisted. Based on the findings of this case, the AngioVac device is a safe and effective treatment option for tricuspid valve endocarditis patients with large vegetation and severe comorbidities, which contraindicate open heart surgery.