Abstract Objectives: Uncertainty pervades the complex illness trajectories experienced by older adults with multimorbidity. Uncertainty is experienced by older people, their informal carers, and professionals providing care, yet is incompletely understood. We aimed to identify and synthesise systematically the experience of uncertainty in advanced multimorbidity from patient, carer and professional perspectives. Design: Systematic literature review of published and grey qualitative literature from 9 databases (Prospero CRD 42021227480). Participants: Older people with advanced multimorbidity, and informal carers/professionals providing care to this group. Exclusion criteria: early multimorbidity, insufficient focus on uncertainty. Analysis: Weight-of-Evidence assessment was used to appraise included articles. We undertook thematic synthesis of multi-perspective experiences and response to uncertainty. Results: From 4738 unique search results, we included 44 articles relating to 40 studies. 22 focused on patient experiences of uncertainty (n = 460), 15 on carer experiences (n = 197), and 19 on health professional experiences (n = 490), with 10 exploring multiple perspectives. We identified a shared experience of ‘Total Uncertainty’ across five domains: ‘appraising and managing multiple illnesses’; ‘fragmented care and communication’; ‘feeling overwhelmed’; ‘uncertainty of others’ and ‘continual change’. Participants responded to uncertainty by either active (addressing, avoiding) or passive (accepting) means. Conclusions: The novel concept of “Total Uncertainty” represents a step change in our understanding of illness experience in advanced multimorbidity. Patients, carers and health professionals experienced uncertainty in similar domains, suggesting a shared understanding is feasible. The domains of Total Uncertainty form a useful organising framework for health professionals caring for older adults with multimorbidity.