Immunocompromised (IC) patients face significant challenges in managing COVID-19 due to their heightened susceptibility to severe illness, persistent infections, and the potential development of drug resistance. Studies indicate that IC patients, particularly those with hematologic malignancies (HM), hematopoietic stem cell transplants (HSCTR), or solid organ transplants (SOTR), experience higher mortality rates and worse outcomes compared to the general population, even post-vaccination. The persistence of the virus in these patients, combined with its rapid mutation, further complicates treatment. Recent evidence supports the use of combined neutralizing monoclonal antibodies (mAbs) and direct-acting antivirals (DAAs) as a more effective approach to viral clearance, reducing mortality, and preventing relapses. However, the rise of resistant variants, especially to mAbs, and concerns about the safety of prolonged or intensive therapies pose ongoing challenges. Monotherapies often fail short to address these issues, highlighting the need for early combined therapy (ECT) with mAbs and DAAs. ECT has shown promise in managing COVID-19 in IC individuals by targeting multiple stages of the viral lifecycle, reducing viral load, and clearing infections at earlier stages, which helps mitigate the risks of severe disease and drug resistance. Continued research is essential to refine these treatment protocols, especially as the virus evolves. Although further studies are needed, current findings suggest that ECT may become the standard of care for managing COVID-19 in severely IC patients, offering better clinical outcomes and hindering viral persistence.