Abstract Background There is an urgent need to understand the determinants (i.e., barriers and facilitators) of de-implementation. The purpose of this study was to develop a comprehensive list of determinants of the de-implementation of low-value care from the published literature and to compare this list to determinants identified by a group of stakeholders with lived experience with de-implementation. Methods This was a two-phase multi-method study. First, a systematic review examined published barriers and facilitators to de-implementation. Articles were identified through searches within electronic databases, reference lists and the grey literature. Citations were screened independently and in duplicate and included if they were: 1) written in English; and 2) described a barrier or facilitator to de-implementation of any clinical practice in adults (age ≥ 18 years). ‘Raw text’ determinants cited within included articles were extracted and synthesized into a list of representative determinants using conventional content analysis. Second, semi-structured interviews were conducted with decision-makers (unit managers and medical directors) and healthcare professionals working in adult critical care medicine to explore the overlap between the determinants found in the systematic review to those experienced in critical care medicine. Thematic content analysis was used to identify key themes emerging from the interviews. Results In the systematic review, reviewers included 172 articles from 35,368 unique citations. From 437 raw text barriers and 280 raw text facilitators, content analysis produced 29 distinct barriers and 24 distinct facilitators to de-implementation. Distinct barriers commonly cited within raw text included ‘lack of credible evidence to support de-implementation’ (n = 90, 21%), ‘entrenched norms and clinicians’ resistance to change (n = 43, 21%), and ‘patient demands and preferences’ (n = 28, 6%). Distinct facilitators commonly cited within raw text included ‘stakeholder collaboration and communication’ (n = 43, 15%), and ‘availability of credible evidence’ (n = 33, 12%). From stakeholder interviews, 23 of 29 distinct barriers and 20 of 24 distinct facilitators from the systematic review were cited as key themes relevant to de-implementation in critical care. Conclusions The availability and quality of evidence that identifies a clinical practice as low-value, as well as healthcare professional willingness to change, and stakeholder collaboration are common and important determinants of de-implementation and may serve as targets for future de-implementation initiatives. Trial registration The systematic review was registered in PROSPERO CRD42016050234.