Background: Treatment-resistant depression (TRD) is a highly prevalent condition. It is generally referred to as the failure of at least two or more prior treatments with antidepressants or augmentation therapy with adequate dose and duration. TRD affects the individual’s overall health and social life, in addition to the economic impact associated with the illness. Therefore, this review is focused on examining the financial burden of illness among patients with TRD across different countries and identifying the key drivers for the incremental costs and healthcare resource utilization (HRU). Methods: A literature search was carried out in the PubMed database using relevant MeSH terms. This review included relevant studies published between 2019 & 2024. Results: Overall, 22 studies were included in this review, with the majority based in the United States (n=15). The majority of the patients were females, ranging from 53.1% to 77%, and the mean age of patients with TRD ranged from 37.7±14.4 to 73.1±6.5 years. The mean annual all-cause healthcare cost per patient ranged from 3,190to40,040. The mean annual all-cause indirect costs per patient ranged from 4,199to6,342. Outpatient visits were the frequently utilized healthcare services, especially psychiatric visits and visits to general practitioners or family physicians. The incremental costs were primarily driven by worsening symptom severity, the presence of comorbidities, advancing age, and frequent visits to specialists. Conclusion: Regardless of the factors influencing the cost burden, TRD generally accounts for higher healthcare use and costs compared to individuals with major depressive disorder or without any mental illness. This underscores the need for fostering newer interventions and implementation of multidisciplinary approaches to lessen the cost burden of this condition, in addition to managing it effectively.