Background Non-beneficial treatment is closely tied to inappropriate treatment at the end-of-life. Understanding the interplay between how and why these situations arise in acute care settings according to the various stakeholders is pivotal to informing decision-making and best practice at end-of-life. Aim To define and understand determinants of  non-beneficial and inappropriate treatments for patients with a non-cancer diagnosis, in acute care settings at the end-of-life. Design Systematic review of peer-reviewed studies focusing on the above and conducted in upper-middle- and high-income countries. A narrative synthesis was undertaken, guided by Realist principles. Data sources Cochrane; PubMed; Scopus; Embase; CINAHL; and Web of Science. Results Sixty-six studies (32 qualitative, 28 quantitative, and 6 mixed-methods) were included after screening 4,754 papers. Non-beneficial treatment was largely defined as when the burden of treatment outweighs any benefit to the patient. Inappropriate treatment at the end-of-life was similar to this, but additionally accounted for patient and family preferences. Contexts in which outcomes related to non-beneficial treatment and/or inappropriate treatment occurred were described as veiled by uncertainty, driven by organizational culture, and limited by profiles and characteristics of involved stakeholders. Mechanisms relating to ‘Motivation to Address Conflict & Seek Agreement’ helped to lessen uncertainty around decision-making. Establishing agreement was reliant on ‘Valuing Clear Communication and Sharing of Information’. Reaching consensus was dependent on ‘Choices around Timing & Documenting of end-of-life Decisions’. Conclusion A framework mapping determinants of non-beneficial and inappropriate end-of-life treatment is developed and proposed to be potentially transferable to diverse contexts. Future studies should test and update the framework as an implementation tool. Trial registration PROSPERO Protocol CRD42021214137.