Treatment-resistant depression (TRD) occurs when depressive symptoms persist after a patient has tried at least two antidepressants at an appropriate dose for an adequate length of time, as judged by their clinician. Understanding what it is like to live with and seek care for TRD can inform treatment planning and contribute to health technology assessments for depression-related therapies. Our objective was to systematically review this evidence through an investigation of qualitative literature about the experiences of people who have TRD. We searched MEDLINE, CINAHL, PsycINFO, and the Web of Science Core Collection. Publications eligible for inclusion were English-language primary empirical qualitative studies or the qualitative component of mixed methods studies examining adults’ experiences with TRD or with specific treatment options for TRD. Two reviewers independently screened and extracted data, as well as critically appraised included studies using the Standards for Reporting Qualitative Research (SRQR) instrument. This review was guided by integrative meta-synthesis. Data analysis consisted of a staged coding process similar to grounded theory. The protocol was registered in PROSPERO prior to the search (record ID: CRD42022356813). Sixteen studies were included from screening 18,568 results. Two studies focused on the overall experience of TRD and 14 explored experiences of specific treatments such as ketamine. Patients described the depressive symptoms they experienced, a sense of futility and desperation to find an effective treatment, and their experiences with new, sometimes experimental, therapies including deriving benefits beyond the clinical. Overall, few studies have examined the patient experience of TRD, reflecting the clinical complexity of this patient population. As most literature coalesced around experiences of specific treatments, greater examination of the overall experience of TRD is needed to inform clinical practice, and administrative and funding policy decisions for interventions that may be effective for this patient population. PROSPERO registration number: CRD42022356813.