IntroductionAmphetamine type stimulant (ATS) use and self-harm are both major public health concerns globally. Use of ATS is associated with a range of health and social problems, and has been increasing internationally in the last decade. Self-harm and ATS use share a number of underlying risk factors and occur at elevated rates in marginalised groups with high rates of exposure to trauma. The relationship between self-harm and ATS use is likely complex, and the causal pathway may run in either direction. A comprehensive review, synthesis and analysis of the evidence are warranted to investigate this relationship and inform policy and practice.Methods and analysisWe will search the Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, PsycINFO and Scopus databases for relevant observational studies published in peer-reviewed journals. The initial search was conducted on 5 February 2021, with a final search expected on 1 February 2022. All studies will be independently screened by two reviewers, first on title and abstract, and then on full-text to determine inclusion in the review. We place no restriction on the population that studies investigate, our exposure of interest is both prescription and illicit ATS use, comparators will be those not currently using ATS, and our primary outcome of interest is the prevalence of self-harm. Data will be extracted using a predesigned template, and pooled prevalence and pooled measures of effect for the association between ATS use and self-harm. If sufficient data are available, we will perform multiple meta-analyses to produce pooled measures of effect for each measure of ATS exposure, as well as different population sub-groups. The Methodological Standard for Epidemiological Research scale will be used to assess study quality, and Egger’s test and I2 values will be used to assess publication bias and heterogeneity, respectively.Ethics and disseminationNo ethical approval is required for this review. We will only synthesise information from published studies that were conducted with ethical approval, so no individual participant data will be used. We will disseminate our findings via publication in a peer-reviewed journal, national and international conference presentations, and presentations to stakeholders in the community.Trial registration numberThis study has been registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42021226562).