Abstract Background Stroke is a leading cause of death and disability worldwide. Identifying the aetiology of ischaemic stroke is essential in order to initiate appropriate and timely secondary prevention measures to reduce the risk of recurrence. For the majority of ischaemic strokes, the aetiology can be readily identified, but in at least 30% of cases, the exact aetiology cannot be determined using existing investigative protocols. Such strokes are classed as ‘cryptogenic’ or as a stroke of unknown origin. However, there exists substantial variation in clinical practice when investigating cases of seemingly cryptogenic stroke, often reflecting local service availability and the preferences of treating clinicians. This variation in practice is compounded by the lack of international consensus as to the optimum level and timing of investigations required following a stroke. To address this gap, we aim to systematically review and compare recommendations in evidence-based clinical practice guidelines (CPGs) that relate to the assessment and investigation of the aetiology of ischaemic stroke, and any subsequent diagnosis of cryptogenic stroke. Method We will search for CPGs using electronic databases (MEDLINE, Health Management Information Consortium (HMIC), EMBASE, and CINAHL), relevant websites and search engines (e.g. guideline specific websites, governmental, charitable, and professional practice organisations) and hand-searching of bibliographies and reference lists. Two reviewers will independently screen titles, abstracts and CPGs using a pre-defined relevance criteria form. From each included CPG, we will extract definitions and terms for cryptogenic stroke; recommendations related to assessment and investigation of the aetiology of stroke, including the grade of recommendations and underpinning evidence. The quality of the included CPGs will be assessed using the AGREE II (Appraisal of Guidelines for Research and Evaluation) tool. Recommendations across the CPGs will be summarised descriptively highlighting areas of convergence and divergence between CPGs. Discussion To our knowledge, this will be the first review to systematically compare recommendations of international CPGs on investigating the aetiology of ischaemic stroke. The findings will allow for a better understanding of international perspectives on the optimum level of investigations required following a stroke and thus contribute to achieving greater international consensus on best practice in this important and complex area. Systematic review registration PROSPERO CRD42019127822.