Nurses, midwives and paramedics are the largest collective group of clinical staff in the National Health Service and have some of the highest prevalence of psychological ill-health. Existing literature tends to be profession-specific and focused on individual interventions that place responsibility for good psychological health with nurses, midwives and paramedics themselves. To improve understanding of how, why and in what contexts nurses, midwives and paramedics experience work-related psychological ill-health; and determine which high-quality interventions can be implemented to minimise psychological ill-health in these professions. Realist synthesis methodology consistent with realist and meta-narrative evidence syntheses: evolving standards' reporting guidelines. First round database searching in Medical Literature Analysis and Retrieval System Online Database ALL (via Ovid), cumulative index to nursing and allied health literature database (via EBSCO) and health management information consortium database (via Ovid), was undertaken between February and March 2021, followed by supplementary searching strategies (e.g. hand searching, expert solicitation of key papers). Reverse chronology screening was applied, aimed at retaining 30 relevant papers in each profession. Round two database searches (December 2021) targeted COVID-19-specific literature and literature reviews. No date limits were applied. We built on seven key reports and included 75 papers in the first round (26 nursing, 26 midwifery, 23 paramedic) plus 44 expert solicitation papers, 29 literature reviews and 49 COVID-19 focused articles in the second round. Through the realist synthesis we surfaced 14 key tensions in the literature and identified five key findings, supported by 26 context mechanism and outcome configurations. The key findings identified the following: (1) interventions are fragmented, individual-focused and insufficiently recognise cumulative chronic stressors; (2) it is difficult to promote staff psychological wellness where there is a blame culture; (3) the needs of the system often override staff well-being at work ('serve and sacrifice'); (4) there are unintended personal costs of upholding and implementing values at work; and (5) it is challenging to design, identify and implement interventions to work optimally for diverse staff groups with diverse and interacting stressors. Our realist synthesis strongly suggests the need to improve the systemic working conditions and the working lives of nurses, midwives and paramedics to improve their psychological well-being. Individual, one-off psychological interventions are unlikely to succeed alone. Psychological ill-health is highly prevalent in these staff groups (and can be chronic and cumulative as well as acute) and should be anticipated and prepared for, indeed normalised and expected. Healthcare organisations need to (1) rebalance the working environment to enable healthcare professionals to recover and thrive; (2) invest in multi-level system approaches to promote staff psychological well-being; and use an organisational diagnostic framework, such as the NHS England and NHS Improvement Health and Wellbeing framework, to self-assess and implement a systems approach to staff well-being. Future research should implement, refine and evaluate systemic interventional strategies. Interventions and evaluations should be co-designed with front-line staff and staff experts by experience, and tailored where possible to local, organisational and workforce needs. The literature was not equivalent in size and quality across the three professions and we did not carry out citation searches using hand searching and stakeholder/expert suggestions to augment our sample. This study is registered as PROSPERO CRD42020172420. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020172420. This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR129528) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 9. See the NIHR Funding and Awards website for further award information.