Introduction Antibiotic resistance is one of the most pressing health threats that mankind faces now and in the coming decades. Antibiotic resistance leads to longer hospital stays, higher medical costs and increased mortality. In order to tackle antibiotic resistance, we will implement in our tertiary care university hospital a computerised-decision support system (CDSS) facilitating antibiotic stewardship and an electronic surveillance software (ESS) facilitating infection prevention and control activities. We describe the protocol to evaluate the impact of the CDSS/ESS combination in adult inpatients. Methods and analysis We conduct a pragmatic, prospective, single-centre, before–after uncontrolled study with an interrupted time-series analysis 12 months before and 12 months after the introduction of the CDSS for antibiotic stewardship (APSS) and ESS for infection surveillance (ZINC). APSS and ZINC will assist, respectively, the antibiotic stewardship and the infection prevention and control teams of Nancy University Hospital (France). We will evaluate the impact of the CDSS/ESS on the antibiotic use in adult (≥18 years) inpatients (hospitalised ≥48 hours). The primary outcome is the prescription rate by all healthcare professionals from the hospital of all systemic antibiotics expressed in defined daily doses/1000 patients/month. Concurrently, we will assess the safety of the intervention, its impact on the appropriateness of antibiotic prescriptions and on additional precautions (isolation precautions) as recommended in guidelines, and on bacterial epidemiology (multidrug-resistant bacteria and Clostridioides difficile infections) in the hospital. Finally, we will evaluate the users’ satisfaction and the cost of this intervention from the hospital perspective. Ethics and dissemination The protocol has been approved by the Ethics Committee of Nancy University Hospital and registered on the ClinicalTrials platform. Results will be disseminated through conferences’ presentations and publications in peer-reviewed journals. Trial registration number NCT04976829 .