Purpose: Patients with advanced cancer typically experience multiple concurrent symptoms, which have a detrimental impact on patient outcomes. No studies to date have qualitatively explored advanced cancer patients’ perceptions of multiple symptoms in oncology and palliative care settings. Understanding the experience of multiple symptoms can inform integrated clinical pathways for treating, assessing and reducing symptom burden. This study aims to describe the beliefs, attitudes and experiences of patients with multiple symptoms in advanced cancer. Methods: Semi-structured interviews were conducted with 58 advanced cancer patients (23 inpatients and 35 outpatients), recruited purposively from two palliative care centres and two hospital-based oncology departments in Sydney, Australia. Transcripts were analysed thematically. Results: Six major themes were identified: imminence of death and deterioration (impending death, anticipatory fear); overwhelming loss of control (symptom volatility, debilitating exhaustion, demoralisation, isolation); impinging on autonomy and identity (losing independence, refusal to a diminished self, self-advocacy, reluctance to burden others); psychological adaptation (accepting the impossibility of recovery, seeking distractions, maintaining hope, mindfulness, accommodating self-limitations), burden of self-management responsibility (perpetual self-monitoring, ambiguity in self-report, urgency of decision making, optimising management); and valuing security and empowerment (safety in coordinated care, compassionate care, fear of medical abandonment, dependence on social support). Patients transitioning from oncology to palliative care settings were more vulnerable to self-management burden. Conclusion: Multiple symptoms have a profound impact on patients’ autonomy, function and psychological state. Multiple symptom management and integrated care is needed to empower advanced cancer patients and reduce their struggles with self-management burden, hopelessness, isolation, fear of abandonment and mortality anxieties.