Abstract Background Antimicrobial resistance is a leading global public health threat, with inappropriate use of antimicrobials in healthcare contributing to its development. Given this urgent need, we developed a complex ePrescribing-based Anti-Microbial Stewardship intervention (ePAMS+). Methods ePAMS+ includes educational and organisational behavioural elements, plus guideline-based clinical decision support to aid optimal antimicrobial use in hospital inpatients. ePAMS+ particularly focuses on prompt initiation of antimicrobials, followed by early review once test results are available to facilitate informed decision-making on stopping or switching where appropriate. A mixed-methods feasibility trial of ePAMS+ will take place in two NHS acute hospital care organisations. Qualitative staff interviews and observation of practice will respectively gather staff views on the technical component of ePAMS+ and information on their use of ePAMS+ in routine work. Focus groups will elicit staff and patient views on ePAMS+; one-to-one interviews will discuss antimicrobial stewardship with staff and will record patient experiences of receiving antibiotics and their thoughts on inappropriate prescribing. Qualitative data will be analysed thematically. Fidelity Index development will enable enactment of ePAMS+ to be measured objectively in a subsequent trial assessing the effectiveness of ePAMS+. Quantitative data collection will determine the feasibility of extracting data and deriving key summaries of antimicrobial prescribing; we will quantify variability in the primary outcome, number of antibiotic defined daily doses, to inform the future larger-scale trial design. Discussion This trial is essential to determine the feasibility of implementing the ePAMS+ intervention and measuring relevant outcomes, prior to evaluating its clinical and cost-effectiveness in a full scale hybrid cluster-randomised stepped-wedge clinical trial. Findings will be shared with study sites and with qualitative research participants and will be published in peer-reviewed journals and presented at academic conferences. Trial registration The qualitative and Fidelity Index research were approved by the Health and Research Authority and the North of Scotland Research Ethics Service (ref: 19/NS/0174). The feasibility trial and quantitative analysis (protocol v1.0, 15 December 2021) were approved by the London South East Research Ethics Committee (ref: 22/LO/0204) and registered with ISRCTN (ISRCTN 13429325) on 24 March 2022